Substituted cyclopentanes or cyclopentanones as therapeutic agents

ABSTRACT

The compounds disclosed herein are useful for treating glaucoma, ocular hypertension, and baldness.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.11/619,997, filed Jan. 4, 2007, which claims priority under 35 U.S.C. §120 to Provisional Patent Application No. 60/757,696, filed on Jan. 10,2006.

DESCRIPTION OF THE INVENTION

Ocular hypotensive agents are useful in the treatment of a number ofvarious ocular hypertensive conditions, such as post-surgical andpost-laser trabeculectomy ocular hypertensive episodes, glaucoma, and aspresurgical adjuncts.

Glaucoma is a disease of the eye characterized by increased intraocularpressure. On the basis of its etiology, glaucoma has been classified asprimary or secondary. For example, primary glaucoma in adults(congenital glaucoma) may be either open-angle or acute or chronicangle-closure. Secondary glaucoma results from pre-existing oculardiseases such as uveitis, intraocular tumor or an enlarged cataract.

The underlying causes of primary glaucoma are not yet known. Theincreased intraocular tension is due to the obstruction of aqueous humoroutflow. In chronic open-angle glaucoma, the anterior chamber and itsanatomic structures appear normal, but drainage of the aqueous humor isimpeded. In acute or chronic angle-closure glaucoma, the anteriorchamber is shallow, the filtration angle is narrowed, and the iris mayobstruct the trabecular meshwork at the entrance of the canal ofSchlemm. Dilation of the pupil may push the root of the iris forwardagainst the angle, and may produce pupilary block and thus precipitatean acute attack. Eyes with narrow anterior chamber angles arepredisposed to acute angle-closure glaucoma attacks of various degreesof severity.

Secondary glaucoma is caused by any interference with the flow ofaqueous humor from the posterior chamber into the anterior chamber andsubsequently, into the canal of Schlemm. Inflammatory disease of theanterior segment may prevent aqueous escape by causing completeposterior synechia in iris bombe, and may plug the drainage channel withexudates. Other common causes are intraocular tumors, enlargedcataracts, central retinal vein occlusion, trauma to the eye, operativeprocedures and intraocular hemorrhage.

Considering all types together, glaucoma occurs in about 2% of allpersons over the age of 40 and may be asymptotic for years beforeprogressing to rapid loss of vision. In cases where surgery is notindicated, topical β-adrenoreceptor antagonists have traditionally beenthe drugs of choice for treating glaucoma.

Certain eicosanoids and their derivatives are currently commerciallyavailable for use in glaucoma management. Eicosanoids and derivativesinclude numerous biologically important compounds such as prostaglandinsand their derivatives. Prostaglandins can be described as derivatives ofprostanoic acid which have the following structural formula:

Various types of prostaglandins are known, depending on the structureand substituents carried on the alicyclic ring of the prostanoic acidskeleton. Further classification is based on the number of unsaturatedbonds in the side chain indicated by numerical subscripts after thegeneric type of prostaglandin [e.g. prostaglandin E₁ (PGE₁),prostaglandin E₂ (PGE₂)], and on the configuration of the substituentson the alicyclic ring indicated by α or β [e.g. prostaglandin F_(2α)(PGF_(2β))].

Prostaglandin EP₂ selective agonists are believed to have severalmedical uses. For example, U.S. Pat. No. 6,437,146 teaches the use ofprostaglandin EP₂ selective agonists “for treating or preventinginflammation and pain in joint and muscle (e.g., rheumatoid arthritis,rheumatoid spondylitis, osteoarthritis, gouty arthritis, juvenilearthritis, etc.), inflammatory skin condition (e.g., sunburn, burns,eczema, dermatitis, etc.), inflammatory eye condition (e.g.,conjunctivitis, etc.), lung disorder in which inflammation is involved(e.g., asthma, bronchitis, pigeon fancier's disease, farmer's lung,etc.), condition of the gastrointestinal tract associated withinflammation (e.g., aphthous ulcer, Chrohn's disease, atrophicgastritis, gastritis varialoforme, ulcerative colitis, coeliac disease,regional ileitis, irritable bowel syndrome, etc.), gingivitis,inflammation, pain and tumescence after operation or injury, pyrexia,pain and other conditions associated with inflammation, allergicdisease, systemic lupus crythematosus, scleroderma, polymyositis,tendinitis, bursitis, periarteritis nodose, rheumatic fever, Sjgren'ssyndrome, Behcet disease, thyroiditis, type I diabetes, diabeticcomplication (diabetic microangiopathy, diabetic retinopathy, diabeticneohropathy, etc.), nephrotic syndrome, aplastic anemia, myastheniagravis, uveitis contact dermatitis, psoriasis, Kawasaki disease,sarcoidosis, Hodgkin's disease, Alzheimers disease, kidney dysfunction(nephritis, nephritic syndrome, etc.), liver dysfunction (hepatitis,cirrhosis, etc.), gastrointestinal dysfunction (diarrhea, inflammatorybowel disease, etc.) shock, bone disease characterized by abnormal bonemetabolism such as osteoporosis (especially, postmenopausalosteoporosis), hypercalcemia, hyperparathyroidism, Paget's bonediseases, osteolysis, hypercalcemia of malignancy with or without bonemetastases, rheumatoid arthritis, periodonritis, osteoarthritis,ostealgia, osteopenia, cancer cachexia, calculosis, lithiasis(especially, urolithiasis), solid carcinoma, mesangial proliferativeglomerulonephritis, edema (e.g. cardiac edema, cerebral edema, etc.),hypertension such as malignant hypertension or the like, premenstrualtension, urinary calculus, oliguria such as the one caused by acute orchronic failure, hyperphosphaturia, or the like.”

U.S. Pat. No. 6,710,072 teaches the use of EP2 agonists for thetreatment or prevention of “osteoporosis, constipation, renal disorders,sexual dysfunction, baldness, diabetes, cancer and in disorder of immuneregulation . . . various pathophysiological diseases including acutemyocardial infarction, vascular thrombosis, hypertension, pulmonaryhypertension, ischemic heart disease, congestive heart failure, andangina pectoris.”

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts an exemplary method of preparing certain compoundsdisclosed herein.

FIG. 2 depicts an exemplary method of preparing certain compoundsdisclosed herein.

FIG. 3 depicts an exemplary method of preparing certain compoundsdisclosed herein.

FIG. 4 depicts an exemplary method of preparing certain compoundsdisclosed herein.

FIG. 5 depicts an exemplary method of preparing synthetic intermediatesto certain compounds disclosed herein.

FIG. 6 depicts an exemplary method of preparing certain compoundsdisclosed herein.

FIG. 7 depicts an exemplary method of preparing certain compoundsdisclosed herein.

FIG. 8 depicts an exemplary method of preparing certain compoundsdisclosed herein.

FIG. 9 depicts an exemplary method of preparing certain compoundsdisclosed herein.

FIG. 10 depicts an exemplary method of preparing certain compoundsdisclosed herein.

FIG. 11 depicts an exemplary method of preparing certain compoundsdisclosed herein.

FIG. 12 depicts an exemplary method of preparing synthetic intermediatesto certain compounds disclosed herein.

FIG. 13 depicts an exemplary method of preparing synthetic intermediatesto certain compounds disclosed herein.

FIG. 14 depicts an exemplary method of preparing certain compoundsdisclosed herein.

FIG. 15 depicts an exemplary method of preparing synthetic intermediatesto certain compounds disclosed herein.

FIG. 16 depicts an exemplary method of preparing certain compoundsdisclosed herein.

One embodiment is a compound according to the formula

or a pharmaceutically acceptable salt or a prodrug thereof.

In another embodiment, said compound, salt thereof, and/or prodrugthereof is used to treat and/or prevent glaucoma and/or ocularhypertension in a mammal.

In another embodiment, said compound, and/or salt thereof, and/orprodrug thereof is used in the manufacture of a medicament for thetreatment and/or prevention of glaucoma and/or ocular hypertension in amammal.

Another embodiment is a composition comprising said compound, and/orsalt thereof, and/or prodrug thereof, wherein said composition isophthalmically acceptable.

Use of this compound in the treatment and/or prevention, and/or in themanufacture of a medicament for the treatment and/or prevention, of anydisease and/or condition mentioned herein as related to prostaglandinEP2 activity is also contemplated.

Another embodiment is a compound according to the formula

or a pharmaceutically acceptable salt or a prodrug thereof.

In another embodiment, said compound, salt thereof, and/or prodrugthereof is used to treat and/or prevent glaucoma and/or ocularhypertension in a mammal.

In another embodiment, said compound, and/or salt thereof, and/orprodrug thereof is used in the manufacture of a medicament for thetreatment and/or prevention of glaucoma and/or ocular hypertension in amammal.

Another embodiment is a composition comprising said compound, and/orsalt thereof, and/or prodrug thereof, wherein said composition isophthalmically acceptable. Use of this compound in the treatment and/orprevention, and/or in the manufacture of a medicament for the treatmentand/or prevention, of any disease and/or condition mentioned herein asrelated to prostaglandin EP2 activity is also contemplated.

Another embodiment is a compound according to the formula

or a pharmaceutically acceptable salt or a prodrug thereof.

In another embodiment, said compound, salt thereof, and/or prodrugthereof is used to treat and/or prevent glaucoma and/or ocularhypertension in a mammal.

In another embodiment, said compound, and/or salt thereof, and/orprodrug thereof is used in the manufacture of a medicament for thetreatment and/or prevention of glaucoma and/or ocular hypertension in amammal.

Another embodiment is a composition comprising said compound, and/orsalt thereof, and/or prodrug thereof, wherein said composition isophthalmically acceptable.

Use of this compound in the treatment and/or prevention, and/or in themanufacture of a medicament for the treatment and/or prevention, of anydisease and/or condition mentioned herein as related to prostaglandinEP2 activity is also contemplated.

Another embodiment is a compound according to the formula

or a pharmaceutically acceptable salt or a prodrug thereof.

In another embodiment, said compound, salt thereof, and/or prodrugthereof is used to treat and/or prevent glaucoma and/or ocularhypertension in a mammal.

In another embodiment, said compound, and/or salt thereof, and/orprodrug thereof is used in the manufacture of a medicament for thetreatment and/or prevention of glaucoma and/or ocular hypertension in amammal.

Another embodiment is a composition comprising said compound, and/orsalt thereof, and/or prodrug thereof, wherein said composition isophthalmically acceptable.

Use of this compound in the treatment and/or prevention, and/or in themanufacture of a medicament for the treatment and/or prevention, of anydisease and/or condition mentioned herein as related to prostaglandinEP2 activity is also contemplated.

Another embodiment is a compound according to the formula

or a pharmaceutically acceptable salt or a prodrug thereof.

In another embodiment, said compound, salt thereof, and/or prodrugthereof is used to treat and/or prevent glaucoma and/or ocularhypertension in a mammal.

In another embodiment, said compound, and/or salt thereof, and/orprodrug thereof is used in the manufacture of a medicament for thetreatment and/or prevention of glaucoma and/or ocular hypertension in amammal.

Another embodiment is a composition comprising said compound, and/orsalt thereof, and/or prodrug thereof, wherein said composition isophthalmically acceptable.

Use of this compound in the treatment and/or prevention, and/or in themanufacture of a medicament for the treatment and/or prevention, of anydisease and/or condition mentioned herein as related to prostaglandinEP2 activity is also contemplated.

Another embodiment is a compound according to the formula

or a pharmaceutically acceptable salt or a prodrug thereof.

In another embodiment, said compound, salt thereof, and/or prodrugthereof is used to treat and/or prevent glaucoma and/or ocularhypertension in a mammal.

In another embodiment, said compound, and/or salt thereof, and/orprodrug thereof is used in the manufacture of a medicament for thetreatment and/or prevention of glaucoma and/or ocular hypertension in amammal.

Another embodiment is a composition comprising said compound, and/orsalt thereof, and/or prodrug thereof, wherein said composition isophthalmically acceptable.

Use of this compound in the treatment and/or prevention, and/or in themanufacture of a medicament for the treatment and/or prevention, of anydisease and/or condition mentioned herein as related to prostaglandinEP2 activity is also contemplated.

Another embodiment is a compound according to the formula

or a pharmaceutically acceptable salt or a prodrug thereof.

In another embodiment, said compound, salt thereof, and/or prodrugthereof is used to treat and/or prevent glaucoma and/or ocularhypertension in a mammal.

In another embodiment, said compound, and/or salt thereof, and/orprodrug thereof is used in the manufacture of a medicament for thetreatment and/or prevention of glaucoma and/or ocular hypertension in amammal.

Another embodiment is a composition comprising said compound, and/orsalt thereof, and/or prodrug thereof, wherein said composition isophthalmically acceptable.

Use of this compound in the treatment and/or prevention, and/or in themanufacture of a medicament for the treatment and/or prevention, of anydisease and/or condition mentioned herein as related to prostaglandinEP2 activity is also contemplated.

Another embodiment is a compound according to the formula

or a pharmaceutically acceptable salt or a prodrug thereof.

In another embodiment, said compound, salt thereof, and/or prodrugthereof is used to treat and/or prevent glaucoma and/or ocularhypertension in a mammal.

In another embodiment, said compound, and/or salt thereof, and/orprodrug thereof is used in the manufacture of a medicament for thetreatment and/or prevention of glaucoma and/or ocular hypertension in amammal.

Another embodiment is a composition comprising said compound, and/orsalt thereof, and/or prodrug thereof, wherein said composition isophthalmically acceptable.

Use of this compound in the treatment and/or prevention, and/or in themanufacture of a medicament for the treatment and/or prevention, of anydisease and/or condition mentioned herein as related to prostaglandinEP2 activity is also contemplated.

Another embodiment is a compound according to the formula

or a pharmaceutically acceptable salt or a prodrug thereof.

In another embodiment, said compound, salt thereof, and/or prodrugthereof is used to treat and/or prevent glaucoma and/or ocularhypertension in a mammal.

In another embodiment, said compound, and/or salt thereof, and/orprodrug thereof is used in the manufacture of a medicament for thetreatment and/or prevention of glaucoma and/or ocular hypertension in amammal.

Another embodiment is a composition comprising said compound, and/orsalt thereof, and/or prodrug thereof, wherein said composition isophthalmically acceptable.

Use of this compound in the treatment and/or prevention, and/or in themanufacture of a medicament for the treatment and/or prevention, of anydisease and/or condition mentioned herein as related to prostaglandinEP2 activity is also contemplated.

Another embodiment is a compound according to the formula

or a pharmaceutically acceptable salt or a prodrug thereof.

In another embodiment, said compound, salt thereof, and/or prodrugthereof is used to treat and/or prevent glaucoma and/or ocularhypertension in a mammal.

In another embodiment, said compound, and/or salt thereof, and/orprodrug thereof is used in the manufacture of a medicament for thetreatment and/or prevention of glaucoma and/or ocular hypertension in amammal.

Another embodiment is a composition comprising said compound, and/orsalt thereof, and/or prodrug thereof, wherein said composition isophthalmically acceptable.

Use of this compound in the treatment and/or prevention, and/or in themanufacture of a medicament for the treatment and/or prevention, of anydisease and/or condition mentioned herein as related to prostaglandinEP2 activity is also contemplated.

Another embodiment is a compound according to the formula

or a pharmaceutically acceptable salt or a prodrug thereof.

In another embodiment, said compound, salt thereof, and/or prodrugthereof is used to treat and/or prevent glaucoma and/or ocularhypertension in a mammal.

In another embodiment, said compound, and/or salt thereof, and/orprodrug thereof is used in the manufacture of a medicament for thetreatment and/or prevention of glaucoma and/or ocular hypertension in amammal.

Another embodiment is a composition comprising said compound, and/orsalt thereof, and/or prodrug thereof, wherein said composition isophthalmically acceptable.

Use of this compound in the treatment and/or prevention, and/or in themanufacture of a medicament for the treatment and/or prevention, of anydisease and/or condition mentioned herein as related to prostaglandinEP2 activity is also contemplated.

Another embodiment is a compound according to the formula

or a pharmaceutically acceptable salt or a prodrug thereof.

In another embodiment, said compound, salt thereof, and/or prodrugthereof is used to treat and/or prevent glaucoma and/or ocularhypertension in a mammal.

In another embodiment, said compound, and/or salt thereof, and/orprodrug thereof is used in the manufacture of a medicament for thetreatment and/or prevention of glaucoma and/or ocular hypertension in amammal.

Another embodiment is a composition comprising said compound, and/orsalt thereof, and/or prodrug thereof, wherein said composition isophthalmically acceptable.

Use of this compound in the treatment and/or prevention, and/or in themanufacture of a medicament for the treatment and/or prevention, of anydisease and/or condition mentioned herein as related to prostaglandinEP2 activity is also contemplated.

Another embodiment is a compound according to the formula

or a pharmaceutically acceptable salt or a prodrug thereof.

In another embodiment, said compound, salt thereof, and/or prodrugthereof is used to treat and/or prevent glaucoma and/or ocularhypertension in a mammal.

In another embodiment, said compound, and/or salt thereof, and/orprodrug thereof is used in the manufacture of a medicament for thetreatment and/or prevention of glaucoma and/or ocular hypertension in amammal.

Another embodiment is a composition comprising said compound, and/orsalt thereof, and/or prodrug thereof, wherein said composition isophthalmically acceptable.

Use of this compound in the treatment and/or prevention, and/or in themanufacture of a medicament for the treatment and/or prevention, of anydisease and/or condition mentioned herein as related to prostaglandinEP2 activity is also contemplated.

Another embodiment is a compound according to the formula

or a pharmaceutically acceptable salt or a prodrug thereof.

In another embodiment, said compound, salt thereof, and/or prodrugthereof is used to treat and/or prevent glaucoma and/or ocularhypertension in a mammal.

In another embodiment, said compound, and/or salt thereof, and/orprodrug thereof is used in the manufacture of a medicament for thetreatment and/or prevention of glaucoma and/or ocular hypertension in amammal.

Another embodiment is a composition comprising said compound, and/orsalt thereof, and/or prodrug thereof, wherein said composition isophthalmically acceptable.

Use of this compound in the treatment and/or prevention, and/or in themanufacture of a medicament for the treatment and/or prevention, of anydisease and/or condition mentioned herein as related to prostaglandinEP2 activity is also contemplated.

Another embodiment is a compound according to the formula

or a pharmaceutically acceptable salt or a prodrug thereof.

In another embodiment, said compound, salt thereof, and/or prodrugthereof is used to treat and/or prevent glaucoma and/or ocularhypertension in a mammal.

In another embodiment, said compound, and/or salt thereof, and/orprodrug thereof is used in the manufacture of a medicament for thetreatment and/or prevention of glaucoma and/or ocular hypertension in amammal.

Another embodiment is a composition comprising said compound, and/orsalt thereof, and/or prodrug thereof, wherein said composition isophthalmically acceptable.

Use of this compound in the treatment and/or prevention, and/or in themanufacture of a medicament for the treatment and/or prevention, of anydisease and/or condition mentioned herein as related to prostaglandinEP2 activity is also contemplated.

Another embodiment is a compound according to the formula

or a pharmaceutically acceptable salt or a prodrug thereof.

In another embodiment, said compound, salt thereof, and/or prodrugthereof is used to treat and/or prevent glaucoma and/or ocularhypertension in a mammal.

In another embodiment, said compound, and/or salt thereof, and/orprodrug thereof is used in the manufacture of a medicament for thetreatment and/or prevention of glaucoma and/or ocular hypertension in amammal.

Another embodiment is a composition comprising said compound, and/orsalt thereof, and/or prodrug thereof, wherein said composition isophthalmically acceptable.

Use of this compound in the treatment and/or prevention, and/or in themanufacture of a medicament for the treatment and/or prevention, of anydisease and/or condition mentioned herein as related to prostaglandinEP2 activity is also contemplated.

Another embodiment is a compound according to the formula

or a pharmaceutically acceptable salt or a prodrug thereof.

In another embodiment, said compound, salt thereof, and/or prodrugthereof is used to treat and/or prevent glaucoma and/or ocularhypertension in a mammal.

In another embodiment, said compound, and/or salt thereof, and/orprodrug thereof is used in the manufacture of a medicament for thetreatment and/or prevention of glaucoma and/or ocular hypertension in amammal.

Another embodiment is a composition comprising said compound, and/orsalt thereof, and/or prodrug thereof, wherein said composition isophthalmically acceptable.

Use of this compound in the treatment and/or prevention, and/or in themanufacture of a medicament for the treatment and/or prevention, of anydisease and/or condition mentioned herein as related to prostaglandinEP2 activity is also contemplated.

Another embodiment is a compound according to the formula

or a pharmaceutically acceptable salt or a prodrug thereof.

In another embodiment, said compound, salt thereof, and/or prodrugthereof is used to treat and/or prevent glaucoma and/or ocularhypertension in a mammal.

In another embodiment, said compound, and/or salt thereof, and/orprodrug thereof is used in the manufacture of a medicament for thetreatment and/or prevention of glaucoma and/or ocular hypertension in amammal.

Another embodiment is a composition comprising said compound, and/orsalt thereof, and/or prodrug thereof, wherein said composition isophthalmically acceptable.

Use of this compound in the treatment and/or prevention, and/or in themanufacture of a medicament for the treatment and/or prevention, of anydisease and/or condition mentioned herein as related to prostaglandinEP2 activity is also contemplated.

Another embodiment is a compound according to the formula

or a pharmaceutically acceptable salt or a prodrug thereof.

In another embodiment, said compound, salt thereof, and/or prodrugthereof is used to treat and/or prevent glaucoma and/or ocularhypertension in a mammal.

In another embodiment, said compound, and/or salt thereof, and/orprodrug thereof is used in the manufacture of a medicament for thetreatment and/or prevention of glaucoma and/or ocular hypertension in amammal.

Another embodiment is a composition comprising said compound, and/orsalt thereof, and/or prodrug thereof, wherein said composition isophthalmically acceptable.

Use of this compound in the treatment and/or prevention, and/or in themanufacture of a medicament for the treatment and/or prevention, of anydisease and/or condition mentioned herein as related to prostaglandinEP2 activity is also contemplated.

Another embodiment is a compound according to the formula

or a pharmaceutically acceptable salt or a prodrug thereof.

In another embodiment, said compound, salt thereof, and/or prodrugthereof is used to treat and/or prevent glaucoma and/or ocularhypertension in a mammal.

In another embodiment, said compound, and/or salt thereof, and/orprodrug thereof is used in the manufacture of a medicament for thetreatment and/or prevention of glaucoma and/or ocular hypertension in amammal.

Another embodiment is a composition comprising said compound, and/orsalt thereof, and/or prodrug thereof, wherein said composition isophthalmically acceptable.

Use of this compound in the treatment and/or prevention, and/or in themanufacture of a medicament for the treatment and/or prevention, of anydisease and/or condition mentioned herein as related to prostaglandinEP2 activity is also contemplated.

Another embodiment is a compound according to the formula

or a pharmaceutically acceptable salt or a prodrug thereof.

In another embodiment, said compound, salt thereof, and/or prodrugthereof is used to treat and/or prevent glaucoma and/or ocularhypertension in a mammal.

In another embodiment, said compound, and/or salt thereof, and/orprodrug thereof is used in the manufacture of a medicament for thetreatment and/or prevention of glaucoma and/or ocular hypertension in amammal.

Another embodiment is a composition comprising said compound, and/orsalt thereof, and/or prodrug thereof, wherein said composition isophthalmically acceptable.

Use of this compound in the treatment and/or prevention, and/or in themanufacture of a medicament for the treatment and/or prevention, of anydisease and/or condition mentioned herein as related to prostaglandinEP2 activity is also contemplated.

Another embodiment is a compound according to the formula

or a pharmaceutically acceptable salt or a prodrug thereof.

In another embodiment, said compound, salt thereof, and/or prodrugthereof is used to treat and/or prevent glaucoma and/or ocularhypertension in a mammal.

In another embodiment, said compound, and/or salt thereof, and/orprodrug thereof is used in the manufacture of a medicament for thetreatment and/or prevention of glaucoma and/or ocular hypertension in amammal.

Another embodiment is a composition comprising said compound, and/orsalt thereof, and/or prodrug thereof, wherein said composition isophthalmically acceptable.

Use of this compound in the treatment and/or prevention, and/or in themanufacture of a medicament for the treatment and/or prevention, of anydisease and/or condition mentioned herein as related to prostaglandinEP2 activity is also contemplated.

Another embodiment is a compound according to the formula

or a pharmaceutically acceptable salt or a prodrug thereof.

In another embodiment, said compound, salt thereof, and/or prodrugthereof is used to treat and/or prevent glaucoma and/or ocularhypertension in a mammal.

In another embodiment, said compound, and/or salt thereof, and/orprodrug thereof is used in the manufacture of a medicament for thetreatment and/or prevention of glaucoma and/or ocular hypertension in amammal.

Another embodiment is a composition comprising said compound, and/orsalt thereof, and/or prodrug thereof, wherein said composition isophthalmically acceptable.

Use of this compound in the treatment and/or prevention, and/or in themanufacture of a medicament for the treatment and/or prevention, of anydisease and/or condition mentioned herein as related to prostaglandinEP2 activity is also contemplated.

Another embodiment is a compound according to the formula

or a pharmaceutically acceptable salt or a prodrug thereof.

In another embodiment, said compound, salt thereof, and/or prodrugthereof is used to treat and/or prevent glaucoma and/or ocularhypertension in a mammal.

In another embodiment, said compound, and/or salt thereof, and/orprodrug thereof is used in the manufacture of a medicament for thetreatment and/or prevention of glaucoma and/or ocular hypertension in amammal.

Another embodiment is a composition comprising said compound, and/orsalt thereof, and/or prodrug thereof, wherein said composition isophthalmically acceptable.

Use of this compound in the treatment and/or prevention, and/or in themanufacture of a medicament for the treatment and/or prevention, of anydisease and/or condition mentioned herein as related to prostaglandinEP2 activity is also contemplated.

Another embodiment is a compound according to the formula

or a pharmaceutically acceptable salt or a prodrug thereof.

In another embodiment, said compound, salt thereof, and/or prodrugthereof is used to treat and/or prevent glaucoma and/or ocularhypertension in a mammal.

In another embodiment, said compound, and/or salt thereof, and/orprodrug thereof is used in the manufacture of a medicament for thetreatment and/or prevention of glaucoma and/or ocular hypertension in amammal.

Another embodiment is a composition comprising said compound, and/orsalt thereof, and/or prodrug thereof, wherein said composition isophthalmically acceptable.

Use of this compound in the treatment and/or prevention, and/or in themanufacture of a medicament for the treatment and/or prevention, of anydisease and/or condition mentioned herein as related to prostaglandinEP2 activity is also contemplated.

Another embodiment is a compound according to the formula

or a pharmaceutically acceptable salt or a prodrug thereof.

In another embodiment, said compound, salt thereof, and/or prodrugthereof is used to treat and/or prevent glaucoma and/or ocularhypertension in a mammal.

In another embodiment, said compound, and/or salt thereof, and/orprodrug thereof is used in the manufacture of a medicament for thetreatment and/or prevention of glaucoma and/or ocular hypertension in amammal.

Another embodiment is a composition comprising said compound, and/orsalt thereof, and/or prodrug thereof, wherein said composition isophthalmically acceptable.

Use of this compound in the treatment and/or prevention, and/or in themanufacture of a medicament for the treatment and/or prevention, of anydisease and/or condition mentioned herein as related to prostaglandinEP2 activity is also contemplated.

Another embodiment is a compound according to the formula

or a pharmaceutically acceptable salt or a prodrug thereof.

In another embodiment, said compound, salt thereof, and/or prodrugthereof is used to treat and/or prevent glaucoma and/or ocularhypertension in a mammal.

In another embodiment, said compound, and/or salt thereof, and/orprodrug thereof is used in the manufacture of a medicament for thetreatment and/or prevention of glaucoma and/or ocular hypertension in amammal.

Another embodiment is a composition comprising said compound, and/orsalt thereof, and/or prodrug thereof, wherein said composition isophthalmically acceptable.

Use of this compound in the treatment and/or prevention, and/or in themanufacture of a medicament for the treatment and/or prevention, of anydisease and/or condition mentioned herein as related to prostaglandinEP2 activity is also contemplated.

Another embodiment is a compound according to the formula

or a pharmaceutically acceptable salt or a prodrug thereof.In another embodiment, said compound, salt thereof, and/or prodrugthereof is used to treat and/or prevent glaucoma and/or ocularhypertension in a mammal.

In another embodiment, said compound, and/or salt thereof, and/orprodrug thereof is used in the manufacture of a medicament for thetreatment and/or prevention of glaucoma and/or ocular hypertension in amammal.

Another embodiment is a composition comprising said compound, and/orsalt thereof, and/or prodrug thereof, wherein said composition isophthalmically acceptable.

Use of this compound in the treatment and/or prevention, and/or in themanufacture of a medicament for the treatment and/or prevention, of anydisease and/or condition mentioned herein as related to prostaglandinEP2 activity is also contemplated.

Another embodiment is a compound according to the formula

or a pharmaceutically acceptable salt or a prodrug thereof.

In another embodiment, said compound, salt thereof, and/or prodrugthereof is used to treat and/or prevent glaucoma and/or ocularhypertension in a mammal.

In another embodiment, said compound, and/or salt thereof, and/orprodrug thereof is used in the manufacture of a medicament for thetreatment and/or prevention of glaucoma and/or ocular hypertension in amammal.

Another embodiment is a composition comprising said compound, and/orsalt thereof, and/or prodrug thereof, wherein said composition isophthalmically acceptable.

Use of this compound in the treatment and/or prevention, and/or in themanufacture of a medicament for the treatment and/or prevention, of anydisease and/or condition mentioned herein as related to prostaglandinEP2 activity is also contemplated.

Another embodiment is a compound according to the formula

or a pharmaceutically acceptable salt or a prodrug thereof.

In another embodiment, said compound, salt thereof, and/or prodrugthereof is used to treat and/or prevent glaucoma and/or ocularhypertension in a mammal.

In another embodiment, said compound, and/or salt thereof, and/orprodrug thereof is used in the manufacture of a medicament for thetreatment and/or prevention of glaucoma and/or ocular hypertension in amammal.

Another embodiment is a composition comprising said compound, and/orsalt thereof, and/or prodrug thereof, wherein said composition isophthalmically acceptable.

Use of this compound in the treatment and/or prevention, and/or in themanufacture of a medicament for the treatment and/or prevention, of anydisease and/or condition mentioned herein as related to prostaglandinEP2 activity is also contemplated.

Another embodiment is a compound according to the formula

or a pharmaceutically acceptable salt or a prodrug thereof.

In another embodiment, said compound, salt thereof, and/or prodrugthereof is used to treat and/or prevent glaucoma and/or ocularhypertension in a mammal.

In another embodiment, said compound, and/or salt thereof, and/orprodrug thereof is used in the manufacture of a medicament for thetreatment and/or prevention of glaucoma and/or ocular hypertension in amammal.

Another embodiment is a composition comprising said compound, and/orsalt thereof, and/or prodrug thereof, wherein said composition isophthalmically acceptable.

Use of this compound in the treatment and/or prevention, and/or in themanufacture of a medicament for the treatment and/or prevention, of anydisease and/or condition mentioned herein as related to prostaglandinEP2 activity is also contemplated.

Another embodiment is a compound according to the formula

or a pharmaceutically acceptable salt or a prodrug thereof.

In another embodiment, said compound, salt thereof, and/or prodrugthereof is used to treat and/or prevent glaucoma and/or ocularhypertension in a mammal.

In another embodiment, said compound, and/or salt thereof, and/orprodrug thereof is used in the manufacture of a medicament for thetreatment and/or prevention of glaucoma and/or ocular hypertension in amammal.

Another embodiment is a composition comprising said compound, and/orsalt thereof, and/or prodrug thereof, wherein said composition isophthalmically acceptable.

Use of this compound in the treatment and/or prevention, and/or in themanufacture of a medicament for the treatment and/or prevention, of anydisease and/or condition mentioned herein as related to prostaglandinEP2 activity is also contemplated.

Another embodiment is a compound according to the formula

or a pharmaceutically acceptable salt or a prodrug thereof.

In another embodiment, said compound, salt thereof, and/or prodrugthereof is used to treat and/or prevent glaucoma and/or ocularhypertension in a mammal.

In another embodiment, said compound, and/or salt thereof, and/orprodrug thereof is used in the manufacture of a medicament for thetreatment and/or prevention of glaucoma and/or ocular hypertension in amammal.

Another embodiment is a composition comprising said compound, and/orsalt thereof, and/or prodrug thereof, wherein said composition isophthalmically acceptable.

Use of this compound in the treatment and/or prevention, and/or in themanufacture of a medicament for the treatment and/or prevention, of anydisease and/or condition mentioned herein as related to prostaglandinEP2 activity is also contemplated.

Another embodiment is a compound according to the formula

or a pharmaceutically acceptable salt or a prodrug thereof.

In another embodiment, said compound, salt thereof, and/or prodrugthereof is used to treat and/or prevent glaucoma and/or ocularhypertension in a mammal.

In another embodiment, said compound, and/or salt thereof, and/orprodrug thereof is used in the manufacture of a medicament for thetreatment and/or prevention of glaucoma and/or ocular hypertension in amammal.

Another embodiment is a composition comprising said compound, and/orsalt thereof, and/or prodrug thereof, wherein said composition isophthalmically acceptable.

Use of this compound in the treatment and/or prevention, and/or in themanufacture of a medicament for the treatment and/or prevention, of anydisease and/or condition mentioned herein as related to prostaglandinEP2 activity is also contemplated.

Another embodiment is a compound according to the formula

or a pharmaceutically acceptable salt or a prodrug thereof.In another embodiment, said compound, salt thereof, and/or prodrugthereof is used to treat and/or prevent glaucoma and/or ocularhypertension in a mammal.In another embodiment, said compound, and/or salt thereof, and/orprodrug thereof is used in the manufacture of a medicament for thetreatment and/or prevention of glaucoma and/or ocular hypertension in amammal.Another embodiment is a composition comprising said compound, and/orsalt thereof, and/or prodrug thereof, wherein said composition isophthalmically acceptable.Use of this compound in the treatment and/or prevention, and/or in themanufacture of a medicament for the treatment and/or prevention, of anydisease and/or condition mentioned herein as related to prostaglandinEP2 activity is also contemplated.

Another embodiment is a compound according to the formula

or a pharmaceutically acceptable salt or a prodrug thereof.In another embodiment, said compound, salt thereof, and/or prodrugthereof is used to treat and/or prevent glaucoma and/or ocularhypertension in a mammal.In another embodiment, said compound, and/or salt thereof, and/orprodrug thereof is used in the manufacture of a medicament for thetreatment and/or prevention of glaucoma and/or ocular hypertension in amammal.Another embodiment is a composition comprising said compound, and/orsalt thereof, and/or prodrug thereof, wherein said composition isophthalmically acceptable.Use of this compound in the treatment and/or prevention, and/or in themanufacture of a medicament for the treatment and/or prevention, of anydisease and/or condition mentioned herein as related to prostaglandinEP2 activity is also contemplated.

Another embodiment is a compound according to the formula

or a pharmaceutically acceptable salt or a prodrug thereof.

In another embodiment, said compound, salt thereof, and/or prodrugthereof is used to treat and/or prevent glaucoma and/or ocularhypertension in a mammal.

In another embodiment, said compound, and/or salt thereof, and/orprodrug thereof is used in the manufacture of a medicament for thetreatment and/or prevention of glaucoma and/or ocular hypertension in amammal.

Another embodiment is a composition comprising said compound, and/orsalt thereof, and/or prodrug thereof, wherein said composition isophthalmically acceptable.

Use of this compound in the treatment and/or prevention, and/or in themanufacture of a medicament for the treatment and/or prevention, of anydisease and/or condition mentioned herein as related to prostaglandinEP2 activity is also contemplated.

Another embodiment is a compound according to the formula

or a pharmaceutically acceptable salt or a prodrug thereof.

In another embodiment, said compound, salt thereof, and/or prodrugthereof is used to treat and/or prevent glaucoma and/or ocularhypertension in a mammal.

In another embodiment, said compound, and/or salt thereof, and/orprodrug thereof is used in the manufacture of a medicament for thetreatment and/or prevention of glaucoma and/or ocular hypertension in amammal.

Another embodiment is a composition comprising said compound, and/orsalt thereof, and/or prodrug thereof, wherein said composition isophthalmically acceptable.

Use of this compound in the treatment and/or prevention, and/or in themanufacture of a medicament for the treatment and/or prevention, of anydisease and/or condition mentioned herein as related to prostaglandinEP2 activity is also contemplated.

Another embodiment is a compound according to the formula

or a pharmaceutically acceptable salt or a prodrug thereof.

In another embodiment, said compound, salt thereof, and/or prodrugthereof is used to treat and/or prevent glaucoma and/or ocularhypertension in a mammal.

In another embodiment, said compound, and/or salt thereof, and/orprodrug thereof is used in the manufacture of a medicament for thetreatment and/or prevention of glaucoma and/or ocular hypertension in amammal.

Another embodiment is a composition comprising said compound, and/orsalt thereof, and/or prodrug thereof, wherein said composition isophthalmically acceptable.

Use of this compound in the treatment and/or prevention, and/or in themanufacture of a medicament for the treatment and/or prevention, of anydisease and/or condition mentioned herein as related to prostaglandinEP2 activity is also contemplated.

Another embodiment is a compound according to the formula

or a pharmaceutically acceptable salt or a prodrug thereof.

In another embodiment, said compound, salt thereof, and/or prodrugthereof is used to treat and/or prevent glaucoma and/or ocularhypertension in a mammal.

In another embodiment, said compound, and/or salt thereof, and/orprodrug thereof is used in the manufacture of a medicament for thetreatment and/or prevention of glaucoma and/or ocular hypertension in amammal.

Another embodiment is a composition comprising said compound, and/orsalt thereof, and/or prodrug thereof, wherein said composition isophthalmically acceptable.

Use of this compound in the treatment and/or prevention, and/or in themanufacture of a medicament for the treatment and/or prevention, of anydisease and/or condition mentioned herein as related to prostaglandinEP2 activity is also contemplated.

Another embodiment is a compound according to the formula

or a pharmaceutically acceptable salt or a prodrug thereof.

In another embodiment, said compound, salt thereof, and/or prodrugthereof is used to treat and/or prevent glaucoma and/or ocularhypertension in a mammal.

In another embodiment, said compound, and/or salt thereof, and/orprodrug thereof is used in the manufacture of a medicament for thetreatment and/or prevention of glaucoma and/or ocular hypertension in amammal.

Another embodiment is a composition comprising said compound, and/orsalt thereof, and/or prodrug thereof, wherein said composition isophthalmically acceptable.

Use of this compound in the treatment and/or prevention, and/or in themanufacture of a medicament for the treatment and/or prevention, of anydisease and/or condition mentioned herein as related to prostaglandinEP2 activity is also contemplated.

Another embodiment is a compound according to the formula

or a pharmaceutically acceptable salt or a prodrug thereof.

In another embodiment, said compound, salt thereof, and/or prodrugthereof is used to treat and/or prevent glaucoma and/or ocularhypertension in a mammal.

In another embodiment, said compound, and/or salt thereof, and/orprodrug thereof is used in the manufacture of a medicament for thetreatment and/or prevention of glaucoma and/or ocular hypertension in amammal.

Another embodiment is a composition comprising said compound, and/orsalt thereof, and/or prodrug thereof, wherein said composition isophthalmically acceptable.

Use of this compound in the treatment and/or prevention, and/or in themanufacture of a medicament for the treatment and/or prevention, of anydisease and/or condition mentioned herein as related to prostaglandinEP2 activity is also contemplated.

Another embodiment is a compound according to the formula

or a pharmaceutically acceptable salt or a prodrug thereof.

In another embodiment, said compound, salt thereof, and/or prodrugthereof is used to treat and/or prevent glaucoma and/or ocularhypertension in a mammal.

In another embodiment, said compound, and/or salt thereof, and/orprodrug thereof is used in the manufacture of a medicament for thetreatment and/or prevention of glaucoma and/or ocular hypertension in amammal.

Another embodiment is a composition comprising said compound, and/orsalt thereof, and/or prodrug thereof, wherein said composition isophthalmically acceptable.

Use of this compound in the treatment and/or prevention, and/or in themanufacture of a medicament for the treatment and/or prevention, of anydisease and/or condition mentioned herein as related to prostaglandinEP2 activity is also contemplated.

Another embodiment is a compound according to the formula

or a pharmaceutically acceptable salt or a prodrug thereof.

In another embodiment, said compound, salt thereof, and/or prodrugthereof is used to treat and/or prevent glaucoma and/or ocularhypertension in a mammal.

In another embodiment, said compound, and/or salt thereof, and/orprodrug thereof is used in the manufacture of a medicament for thetreatment and/or prevention of glaucoma and/or ocular hypertension in amammal.

Another embodiment is a composition comprising said compound, and/orsalt thereof, and/or prodrug thereof, wherein said composition isophthalmically acceptable.

Use of this compound in the treatment and/or prevention, and/or in themanufacture of a medicament for the treatment and/or prevention, of anydisease and/or condition mentioned herein as related to prostaglandinEP2 activity is also contemplated.

Another embodiment is a compound according to the formula

or a pharmaceutically acceptable salt or a prodrug thereof.

In another embodiment, said compound, salt thereof, and/or prodrugthereof is used to treat and/or prevent glaucoma and/or ocularhypertension in a mammal.

In another embodiment, said compound, and/or salt thereof, and/orprodrug thereof is used in the manufacture of a medicament for thetreatment and/or prevention of glaucoma and/or ocular hypertension in amammal.

Another embodiment is a composition comprising said compound, and/orsalt thereof, and/or prodrug thereof, wherein said composition isophthalmically acceptable.

Use of this compound in the treatment and/or prevention, and/or in themanufacture of a medicament for the treatment and/or prevention, of anydisease and/or condition mentioned herein as related to prostaglandinEP2 activity is also contemplated.

Another embodiment is a compound according to the formula

or a pharmaceutically acceptable salt or a prodrug thereof.

In another embodiment, said compound, salt thereof, and/or prodrugthereof is used to treat and/or prevent glaucoma and/or ocularhypertension in a mammal.

In another embodiment, said compound, and/or salt thereof, and/orprodrug thereof is used in the manufacture of a medicament for thetreatment and/or prevention of glaucoma and/or ocular hypertension in amammal.

Another embodiment is a composition comprising said compound, and/orsalt thereof, and/or prodrug thereof, wherein said composition isophthalmically acceptable.

Use of this compound in the treatment and/or prevention, and/or in themanufacture of a medicament for the treatment and/or prevention, of anydisease and/or condition mentioned herein as related to prostaglandinEP2 activity is also contemplated.

Another embodiment is a compound according to the formula

or a pharmaceutically acceptable salt or a prodrug thereof.

In another embodiment, said compound, salt thereof, and/or prodrugthereof is used to treat and/or prevent glaucoma and/or ocularhypertension in a mammal.

In another embodiment, said compound, and/or salt thereof, and/orprodrug thereof is used in the manufacture of a medicament for thetreatment and/or prevention of glaucoma and/or ocular hypertension in amammal.

Another embodiment is a composition comprising said compound, and/orsalt thereof, and/or prodrug thereof, wherein said composition isophthalmically acceptable.

Use of this compound in the treatment and/or prevention, and/or in themanufacture of a medicament for the treatment and/or prevention, of anydisease and/or condition mentioned herein as related to prostaglandinEP2 activity is also contemplated.

Another embodiment is a compound according to the formula

or a pharmaceutically acceptable salt or a prodrug thereof.

In another embodiment, said compound, salt thereof, and/or prodrugthereof is used to treat and/or prevent glaucoma and/or ocularhypertension in a mammal.

In another embodiment, said compound, and/or salt thereof, and/orprodrug thereof is used in the manufacture of a medicament for thetreatment and/or prevention of glaucoma and/or ocular hypertension in amammal.

Another embodiment is a composition comprising said compound, and/orsalt thereof, and/or prodrug thereof, wherein said composition isophthalmically acceptable.

Use of this compound in the treatment and/or prevention, and/or in themanufacture of a medicament for the treatment and/or prevention, of anydisease and/or condition mentioned herein as related to prostaglandinEP2 activity is also contemplated.

Another embodiment is a compound according to the formula

or a pharmaceutically acceptable salt or a prodrug thereof.

In another embodiment, said compound, salt thereof, and/or prodrugthereof is used to treat and/or prevent glaucoma and/or ocularhypertension in a mammal.

In another embodiment, said compound, and/or salt thereof, and/orprodrug thereof is used in the manufacture of a medicament for thetreatment and/or prevention of glaucoma and/or ocular hypertension in amammal.

Another embodiment is a composition comprising said compound, and/orsalt thereof, and/or prodrug thereof, wherein said composition isophthalmically acceptable.

Use of this compound in the treatment and/or prevention, and/or in themanufacture of a medicament for the treatment and/or prevention, of anydisease and/or condition mentioned herein as related to prostaglandinEP2 activity is also contemplated.

Another embodiment is a compound according to the formula

or a pharmaceutically acceptable salt or a prodrug thereof.

In another embodiment, said compound, salt thereof, and/or prodrugthereof is used to treat and/or prevent glaucoma and/or ocularhypertension in a mammal.

In another embodiment, said compound, and/or salt thereof, and/orprodrug thereof is used in the manufacture of a medicament for thetreatment and/or prevention of glaucoma and/or ocular hypertension in amammal.

Another embodiment is a composition comprising said compound, and/orsalt thereof, and/or prodrug thereof, wherein said composition isophthalmically acceptable.

Use of this compound in the treatment and/or prevention, and/or in themanufacture of a medicament for the treatment and/or prevention, of anydisease and/or condition mentioned herein as related to prostaglandinEP2 activity is also contemplated.

Another embodiment is a compound according to the formula

or a pharmaceutically acceptable salt or a prodrug thereof.

In another embodiment, said compound, salt thereof, and/or prodrugthereof is used to treat and/or prevent glaucoma and/or ocularhypertension in a mammal.

In another embodiment, said compound, and/or salt thereof, and/orprodrug thereof is used in the manufacture of a medicament for thetreatment and/or prevention of glaucoma and/or ocular hypertension in amammal.

Another embodiment is a composition comprising said compound, and/orsalt thereof, and/or prodrug thereof, wherein said composition isophthalmically acceptable.

Use of this compound in the treatment and/or prevention, and/or in themanufacture of a medicament for the treatment and/or prevention, of anydisease and/or condition mentioned herein as related to prostaglandinEP2 activity is also contemplated.

Another embodiment is a compound according to the formula

or a pharmaceutically acceptable salt or a prodrug thereof.

In another embodiment, said compound, salt thereof, and/or prodrugthereof is used to treat and/or prevent glaucoma and/or ocularhypertension in a mammal.

In another embodiment, said compound, and/or salt thereof, and/orprodrug thereof is used in the manufacture of a medicament for thetreatment and/or prevention of glaucoma and/or ocular hypertension in amammal.

Another embodiment is a composition comprising said compound, and/orsalt thereof, and/or prodrug thereof, wherein said composition isophthalmically acceptable.

Use of this compound in the treatment and/or prevention, and/or in themanufacture of a medicament for the treatment and/or prevention, of anydisease and/or condition mentioned herein as related to prostaglandinEP2 activity is also contemplated.

Each of the compounds listed below are individually embodiments.

-   (Z)-7-[(1R,2S,3R,5R)-2-(3,5-Bis-trifluoromethyl-phenoxymethyl)-5-chloro-3-hydroxy-cyclopentyl]-hept-5-enoic    acid;-   (Z)-7-[(1R,2S,3R,5R)-2-(3,5-Bis-trifluoromethyl-phenoxymethyl)-5-chloro-3-hydroxy-cyclopentyl]-heptanoic    acid;-   (Z)-7-[(1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-(naphthalen-2-yloxymethyl)-cyclopentyl]-hept-5-enoic    acid;-   (Z)-7-[(1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-(naphthalen-2-yloxymethyl)-cyclopentyl]-heptanoic    acid;-   (Z)-7-[(1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-(naphthalen-1-yloxymethyl)-cyclopentyl]-hept-5-enoic    acid;-   (Z)-7-[(1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-(naphthalen-1-yloxymethyl)-cyclopentyl]-heptanoic    acid;-   (Z)-7-[(1R,2S,3R,5R)-5-Chloro-2-(2-chloro-phenoxymethyl)-3-hydroxy-cyclopentyl]-hept-5-enoic    acid;-   (Z)-7-[(1R,2S,3R,5R)-5-Chloro-2-(3-chloro-phenoxymethyl)-3-hydroxy-cyclopentyl]-hept-5-enoic    acid;-   (Z)-7-[(1R,2S,3R,5R)-5-Chloro-2-(4-chloro-phenoxymethyl)-3-hydroxy-cyclopentyl]-hept-5-enoic    acid;-   (Z)-7-[(1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-(3-trifluoromethyl-phenoxymethyl)-cyclopentyl]-hept-5-enoic    acid;-   (Z)-7-((1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-m-tolyloxymethyl-cyclopentyl)-hept-5-enoic    acid;-   (Z)-7-[(1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-(3-isopropyl-phenoxymethyl)-cyclopentyl]-hept-5-enoic    acid;-   (Z)-7-[(1R,2S,3R,5R)-2-(3-tert-Butyl-phenoxymethyl)-5-chloro-3-hydroxy-cyclopentyl]-hept-5-enoic    acid;-   (Z)-7-[(1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-(3-methoxy-phenoxymethyl)-cyclopentyl]-hept-5-enoic    acid;-   3-[(S,2R,3R,5R)-2-((Z)-6-carboxy-hex-2-enyl)-3-chloro-5-hydroxy-cyclopentylmethoxy]-phenyl    benzoate;-   (Z)-7-[(1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-(3-hydroxy-phenoxymethyl)-cyclopentyl]-hept-5-enoic    acid;-   (Z)-7-{(1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-[4-(1-methyl-1-phenyl-ethyl)-phenoxymethyl]-cyclopentyl}-hept-5-enoic    acid;-   (Z)-7-[(1R,2S,3R,5R)-5-Chloro-2-(2,3-dimethyl-phenoxymethyl)-3-hydroxy-cyclopentyl]-hept-5-enoic    acid;-   (Z)-7-[(1R,2S,3R,5R)-5-Chloro-2-(2,4-dimethyl-phenoxymethyl)-3-hydroxy-cyclopentyl]-hept-5-enoic    acid;-   (Z)-7-[(1R,2S,3R,5R)-5-Chloro-2-(2,5-dimethyl-phenoxymethyl)-3-hydroxy-cyclopentyl]-hept-5-enoic    acid;-   (Z)-7-[(1R,2S,3R,5R)-5-Chloro-2-(2,6-dimethyl-phenoxymethyl)-3-hydroxy-cyclopentyl]-hept-5-enoic    acid;-   (Z)-7-[(1R,2S,3R,5R)-5-Chloro-2-(3,5-dimethyl-phenoxymethyl)-3-hydroxy-cyclopentyl]-hept-5-enoic    acid;-   (Z)-7-[(1R,2S,3R,5R)-5-Chloro-2-(3,4-dimethyl-phenoxymethyl)-3-hydroxy-cyclopentyl]-hept-5-enoic    acid;-   (Z)-7-[(1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-(3,4,5-trimethyl-phenoxymethyl)-cyclopentyl]-hept-5-enoic    acid;-   (Z)-7-[(1R,2S,3R,5R)-5-Chloro-2-(4-chloro-3,5-dimethyl-phenoxymethyl)-3-hydroxy-cyclopentyl]-hept-5-enoic    acid;-   (Z)-7-[(1R,2S,3R,5R)-5-Chloro-2-(4-chloro-naphthalen-1-yloxymethyl)-3-hydroxy-cyclopentyl]-hept-5-enoic    acid;-   (Z)-7-[(1R,2S,3R,5R)-5-Chloro-2-(3-chloro-2-fluoro-5-trifluoromethyl-phenoxymethyl)-3-hydroxy-cyclopentyl]-hept-5-enoic    acid;-   (Z)-7-[(1R,2S,3R,5R)-5-Chloro-2-(4-formyl-phenoxymethyl)-3-hydroxy-cyclopentyl]-hept-5-enoic    acid;-   (Z)-7-[(1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-(4-hydroxymethyl-phenoxymethyl)-cyclopentyl]-hept-5-enoic    acid;-   (Z)-7-{(1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-[4-(1-hydroxy-butyl)-phenoxymethyl]-cyclopentyl}-hept-5-enoic    acid;-   (Z)-7-{(1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-[4-(1-methoxy-butyl)-phenoxymethyl]-cyclopentyl}-hept-5-enoic    acid;-   (Z)-7-{(1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-[4-(1-hydroxy-hexyl)-phenoxymethyl]-cyclopentyl}-hept-5-enoic    acid;-   (Z)-7-{(1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-[4-(1-hydroxy-ethyl)-phenoxymethyl]-cyclopentyl}-hept-5-enoic    acid;-   (Z)-7-[(1R,2S,3R,5R)-5-Chloro-2-(3-formyl-phenoxymethyl)-3-hydroxy-cyclopentyl]-hept-5-enoic    acid;-   (Z)-7-[(1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-(3-hydroxymethyl-phenoxymethyl)-cyclopentyl]-hept-5-enoic    acid;-   (Z)-7-{(1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-[3-(1-hydroxy-hexyl)-phenoxymethyl]-cyclopentyl}-hept-5-enoic    acid;-   (Z)-7-{(1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-[3-(1-hydroxy-2-methyl-propyl)-phenoxymethyl]-cyclopentyl}-hept-5-enoic    acid;-   (Z)-7-{(1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-[3-(1-hydroxy-butyl)-phenoxymethyl]-cyclopentyl}-hept-5-enoic    acid;-   (Z)-7-{(1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-[3-(1-hydroxy-2-phenyl-ethyl)-phenoxymethyl]-cyclopentyl}-hept-5-enoic    acid;-   (Z)-7-{(1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-[3-(1-hydroxy-ethyl)-phenoxymethyl]-cyclopentyl}-hept-5-enoic    acid;-   (Z)-7-[(1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-(2-hydroxymethyl-phenoxymethyl)-cyclopentyl]-hept-5-enoic    acid;-   (Z)-7-[(1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-(4-hydroxymethyl-3,5-dimethyl-phenoxymethyl)-cyclopentyl]-hept-5-enoic    acid;-   (Z)-7-[(1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-(4-methoxymethyl-3,5-dimethyl-phenoxymethyl)-cyclopentyl]-hept-5-enoic    acid;-   (Z)-7-[(1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-(1-oxo-indan-4-yloxymethyl)-cyclopentyl]-hept-5-enoic    acid;-   (Z)-7-[(1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-(1-hydroxy-indan-4-yloxymethyl)-cyclopentyl]-hept-5-enoic    acid;-   (Z)-7-[(1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-(5-hydroxy-5,6,7,8-tetrahydro-naphthalen-1-yloxymethyl)-cyclopentyl]-hept-5-enoic    acid;-   (Z)-7-{(1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-[2-(2-hydroxy-ethyl)-phenoxymethyl]-cyclopentyl}-hept-5-enoic    acid;-   (Z)-7-{(1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-[3-(2-hydroxy-ethyl)-phenoxymethyl]-cyclopentyl}-hept-5-enoic    acid;-   (Z)-7-{(1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-[4-(2-hydroxy-ethyl)-phenoxymethyl]-cyclopentyl}-hept-5-enoic    acid;-   (Z)-7-[(1R,2S,3R,5R)-2-(3-Acetoxymethyl-5-chloro-phenoxymethyl)-5-chloro-3-hydroxy-cyclopentyl]-hept-5-enoic    acid;-   (Z)-7-[(1R,2S,3R,5R)-5-Chloro-2-(3-chloro-5-hydroxymethyl-phenoxymethyl)-3-hydroxy-cyclopentyl]-hept-5-enoic    acid;-   (Z)-7-{(1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-[4-(2-hydroxy-ethyl)-3,5-dimethyl-phenoxymethyl]-cyclopentyl}-hept-5-enoic    acid;-   (Z)-7-[(1R,2S,3R,5R)-5-Chloro-2-(3,5-dichloro-phenoxymethyl)-3-hydroxy-cyclopentyl]-hept-5-enoic    acid isopropyl ester;-   (Z)-7-[(1R,2S,3R,5R)-5-Chloro-2-(3,5-dimethyl-phenoxymethyl)-3-hydroxy-cyclopentyl]-hept-5-enoic    acid isopropyl ester;-   (Z)-7-[(1R,2S,3R,5R)-2-(3,5-Bis-trifluoromethyl-phenoxymethyl)-5-chloro-3-hydroxy-cyclopentyl]-hept-5-enoic    acid isopropyl ester;-   (Z)-7-[(1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-(3-trifluoromethyl-phenoxymethyl)-cyclopentyl]-hept-5-enoic    acid isopropyl ester; and-   (Z)-7-[(1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-(4-hydroxymethyl-phenoxymethyl)-cyclopentyl]-hept-5-enoic    acid isopropyl ester.

In another embodiment, said compound, salt thereof, and/or prodrugthereof is used to treat and/or prevent glaucoma and/or ocularhypertension in a mammal.

In another embodiment, said compound, and/or salt thereof, and/orprodrug thereof is used in the manufacture of a medicament for thetreatment and/or prevention of glaucoma and/or ocular hypertension in amammal.

Another embodiment is a composition comprising said compound, and/orsalt thereof, and/or prodrug thereof, wherein said composition isophthalmically acceptable.

Use of this compound in the treatment and/or prevention, and/or in themanufacture of a medicament for the treatment and/or prevention, of anydisease and/or condition mentioned herein as related to prostaglandinEP2 activity is also contemplated.

The compounds disclosed in Table 1 herein are useful for the preventionor treatment of glaucoma or ocular hypertension in mammals, or for themanufacture of a medicament for the treatment of glaucoma or ocularhypertension. They are also useful for the treatment of those diseasesdisclosed in the art as being amenable to treatment by prostaglandin EP₂agonist, such as the ones listed previously.

Each compound of Table 1 is individually and specifically contemplatedas an embodiment. Furthermore, pharmaceutically acceptable salts orprodrugs of the compounds of Table 1 are also contemplated asembodiments.

Each compound of Table 1 is individually and specifically contemplatedfor the treatment or prevention of glaucoma or ocular hypertension.Furthermore, use of pharmaceutically acceptable salts or prodrugs of thecompounds of Table 1 is also contemplated.

Each compound of Table 1 is individually and specifically contemplatedfor use in the manufacture of a medicament for the treatment orprevention of glaucoma or ocular hypertension. Furthermore, use ofpharmaceutically acceptable salts or prodrugs of the compounds of Table1 is also contemplated.

Each compound of Table 1 is individually and specifically contemplatedfor use in the manufacture of a medicament for the treatment orprevention of glaucoma or ocular hypertension. Furthermore, use ofpharmaceutically acceptable salts or prodrugs of the compounds of Table1 is also contemplated.

A composition which is ophthalmically acceptable is individually andspecifically contemplated for each compound of Table 1, andpharmaceutically acceptable salts thereof, and prodrugs thereof.Furthermore, use of pharmaceutically acceptable salts or prodrugs of thecompounds of Table 1 is also contemplated.

The determination of whether a compound is active at a prostaglandin EP2receptor is well within the ability of a person of ordinary skill in theart. While not intending to limit the scope of the invention in any way,one method of making such a determination is also provided in theexamples herein.

A “pharmaceutically acceptable salt” is any salt that retains theactivity of the parent compound and does not impart any additionaldeleterious or untoward effects on the subject to which it isadministered and in the context in which it is administered compared tothe parent compound. A pharmaceutically acceptable salt also refers toany salt which may form in vivo as a result of administration of anacid, another salt, or a prodrug which is converted into an acid orsalt.

Pharmaceutically acceptable salts of acidic functional groups may bederived from organic or inorganic bases. The salt may comprise a mono orpolyvalent ion. Of particular interest are the inorganic ions, lithium,sodium, potassium, calcium, and magnesium. Organic salts may be madewith amines, particularly ammonium salts such as mono-, di- and trialkylamines or ethanol amines. Salts may also be formed with caffeine,tromethamine and similar molecules. Hydrochloric acid or some otherpharmaceutically acceptable acid may form a salt with a compound thatincludes a basic group, such as an amine or a pyridine ring.

A “prodrug” is a compound which is converted to a therapeutically activecompound after administration, and the term should be interpreted asbroadly herein as is generally understood in the art. While notintending to limit the scope of the invention, conversion may occur byhydrolysis of an ester group or some other biologically labile group.Generally, but not necessarily, a prodrug is inactive or less activethan the therapeutically active compound to which it is converted. Esterprodrugs of the compounds disclosed herein are specificallycontemplated. An ester may be derived from a carboxylic acid of C1 (i.e.the terminal carboxylic acid of a natural prostaglandin), or an estermay be derived from a carboxylic acid functional group on another partof the molecule, such as on a phenyl ring. While not intending to belimiting, an ester may be an alkyl ester, an aryl ester, or a heteroarylester. The term alkyl has the meaning generally understood by thoseskilled in the art and refers to linear, branched, or cyclic alkylmoieties. C₁₋₆ alkyl esters are particularly useful, where alkyl part ofthe ester has from 1 to 6 carbon atoms and includes, but is not limitedto, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, iso-butyl,t-butyl, pentyl isomers, hexyl isomers, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, and combinations thereof having from 1-6 carbonatoms, etc.

Those skilled in the art will readily understand that for administrationor the manufacture of medicaments the compounds disclosed herein can beadmixed with pharmaceutically acceptable excipients which per se arewell known in the art. Specifically, a drug to be administeredsystemically, it may be confected as a powder, pill, tablet or the like,or as a solution, emulsion, suspension, aerosol, syrup or elixirsuitable for oral or parenteral administration or inhalation.

For solid dosage forms or medicaments, non-toxic solid carriers include,but are not limited to, pharmaceutical grades of mannitol, lactose,starch, magnesium stearate, sodium saccharin, the polyalkylene glycols,talcum, cellulose, glucose, sucrose and magnesium carbonate. The soliddosage forms may be uncoated or they may be coated by known techniquesto delay disintegration and absorption in the gastrointestinal tract andthereby provide a sustained action over a longer period. For example, atime delay material such as glyceryl monostearate or glyceryl distcaratemay be employed. They may also be coated by the technique described inthe U.S. Pat. Nos. 4,256,108; 4,166,452; and 4,265,874 to form osmotictherapeutic tablets for control release. Liquid pharmaceuticallyadministrable dosage forms can, for example, comprise a solution orsuspension of one or more of the presently useful compounds and optionalpharmaceutical adjutants in a carrier, such as for example, water,saline, aqueous dextrose, glycerol, ethanol and the like, to therebyform a solution or suspension. If desired, the pharmaceuticalcomposition to be administered may also contain minor amounts ofnontoxic auxiliary substances such as wetting or emulsifying agents, pHbuffering agents and the like. Typical examples of such auxiliary agentsare sodium acetate, sorbitan monolaurate, triethanolamine, sodiumacetate, triethanolamine oleate, etc. Actual methods of preparing suchdosage forms are known, or will be apparent, to those skilled in thisart; for example, see Remington's Pharmaceutical Sciences, MackPublishing Company, Easton, Pa., 16th Edition, 1980. The composition ofthe formulation to be administered, in any event, contains a quantity ofone or more of the presently useful compounds in an amount effective toprovide the desired therapeutic effect.

Parenteral administration is generally characterized by injection,either subcutaneously, intramuscularly or intravenously. Injectables canbe prepared in conventional forms, either as liquid solutions orsuspensions, solid forms suitable for solution or suspension in liquidprior to injection, or as emulsions. Suitable excipients are, forexample, water, saline, dextrose, glycerol, ethanol and the like. Inaddition, if desired, the injectable pharmaceutical compositions to beadministered may also contain minor amounts of non-toxic auxiliarysubstances such as wetting or emulsifying agents, pH buffering agentsand the like.

The amount of the presently useful compound or compounds administeredis, of course, dependent on the therapeutic effect or effects desired,on the specific mammal being treated, on the severity and nature of themammal's condition, on the manner of administration, on the potency andpharmacodynamics of the particular compound or compounds employed, andon the judgment of the prescribing physician. The therapeuticallyeffective dosage of the presently useful compound or compounds ispreferably in the range of about 0.5 or about 1 to about 100 mg/kg/day.

A liquid which is ophthalmically acceptable is formulated such that itcan be administered topically to the eye. The comfort should bemaximized as much as possible, although sometimes formulationconsiderations (e.g. drug stability) may necessitate less than optimalcomfort. In the case that comfort cannot be maximized, the liquid shouldbe formulated such that the liquid is tolerable to the patient fortopical ophthalmic use. Additionally, an ophthalmically acceptableliquid should either be packaged for single use, or contain apreservative to prevent contamination over multiple uses.

For ophthalmic application, solutions or medicaments are often preparedusing a physiological saline solution as a major vehicle. Ophthalmicsolutions should preferably be maintained at a comfortable pH with anappropriate buffer system. The formulations may also containconventional, pharmaceutically acceptable preservatives, stabilizers andsurfactants.

Preservatives that may be used in the pharmaceutical compositions of thepresent invention include, but are not limited to, benzalkoniumchloride, chlorobutanol, thimerosal, phenylmercuric acetate andphenylmercuric nitrate. A useful surfactant is, for example, Tween 80.Likewise, various useful vehicles may be used in the ophthalmicpreparations of the present invention. These vehicles include, but arenot limited to, polyvinyl alcohol, povidone, hydroxypropyl methylcellulose, poloxamers, carboxymethyl cellulose, hydroxyethyl celluloseand purified water.

Tonicity adjustors may be added as needed or convenient. They include,but are not limited to, salts, particularly sodium chloride, potassiumchloride, mannitol and glycerin, or any other suitable ophthalmicallyacceptable tonicity adjustor.

Various buffers and means for adjusting pH may be used so long as theresulting preparation is ophthalmically acceptable. Accordingly, buffersinclude acetate buffers, citrate buffers, phosphate buffers and boratebuffers. Acids or bases may be used to adjust the pH of theseformulations as needed.

In a similar vein, an ophthalmically acceptable antioxidant for use inthe present invention includes, but is not limited to, sodiummetabisulfite, sodium thiosulfate, acetylcysteine, butylatedhydroxyanisole and butylated hydroxytoluene.

Other excipient components which may be included in the ophthalmicpreparations are chelating agents. A useful chelating agent is edetatedisodium, although other chelating agents may also be used in place orin conjunction with it.

The ingredients are usually used in the following amounts: IngredientAmount (% w/v) active ingredient about 0.001-5 preservative   0-0.10vehicle 0-40 tonicity adjustor 1-10 buffer 0.01-10   pH adjustor q.s. pH4.5-7.5 antioxidant as needed surfactant as needed purified water asneeded to make 100%

For topical use, creams, ointments, gels, solutions or suspensions,etc., containing the compound disclosed herein are employed. Topicalformulations may generally be comprised of a pharmaceutical carrier,cosolvent, emulsifier, penetration enhancer, preservative system, andemollient. The actual dose of the active compounds of the presentinvention depends on the specific compound, and on the condition to betreated; the selection of the appropriate dose is well within theknowledge of the skilled artisan.

The compounds disclosed herein are also useful in combination with otherdrugs useful for the treatment of glaucoma or other conditions.

For the treatment of glaucoma, combination treatment with the followingclasses of drugs is contemplated:

β-Blockers (or β-adrenergic antagonists) including carteolol,levobunolol, metiparanolol, timolol hemihydrate, timolol maleate,1-selective antagonists such as betaxolol, and the like, orpharmaceutically acceptable salts or prodrugs thereof;

Adrenergic Agonists including

non-selective adrenergic agonists such as epinephrine borate,epinephrine hydrochloride, and dipivefrin, and the like, orpharmaceutically acceptable salts or prodrugs thereof; and

α₂-selective adrenergic agonists such as apraclonidine, brimonidine, andthe like, or pharmaceutically acceptable salts or prodrugs thereof;

Carbonic Anhydrase Inhibitors including acetazolamide, dichlorphenamide,methazolamide, brinzolamide, dorzolamide, and the like, orpharmaceutically acceptable salts or prodrugs thereof;

Cholinergic Agonists including

direct acting cholinergic agonists such as charbachol, pilocarpinehydrochloride, pilocarbine nitrate, pilocarpine, and the like, orpharmaceutically acceptable salts or prodrugs thereof;

chlolinesterase inhibitors such as demecarium, echothiophate,physostigmine, and the like, or pharmaceutically acceptable salts orprodrugs thereof;

Glutamate Antagonists such as memantine, amantadine, rimantadine,nitroglycerin, dextrophan, detromethorphan, CGS-19755, dihydropyridines,verapamil, emopamil, benzothiazepines, bepridil,diphenylbutylpiperidines, diphenylpiperazines, HOE 166 and relateddrugs, fluspirilene, eliprodil, ifenprodil, CP-101,606, tibalosine,2309BT, and 840S, flunarizine, nicardipine, nifedimpine, nimodipine,bamidipine, verapamil, lidoflazine, prenylamine lactate, amiloride, andthe like, or pharmaceutically acceptable salts or prodrugs thereof;

Prostamides such as bimatoprost, or pharmaceutically acceptable salts orprodrugs thereof; and

Prostaglandins including travoprost, UFO-21, chloprostenol,fluprostenol, 13,14-dihydro-chloprostenol, latanoprost and the like.TABLE 1 hEP2 hEP4 Exam- flipr cAMP flipr Other Receptors ple StructureEC50 EC50 Ki EC50 Ki hFP hEP1 hEP3 hTP hIP hDP 15

8 8 12985 2294 NA NA 2800 NA NA 6228 16

40 45 13060 4111 NA NA 1699 NA NA NA 17

27 61 3424 507 NA NA NA NA NA NA 18

65 89 6311 973 NA NA NA NA NA NA 19

2 17 115 315 NA 2202 5867 NA NA NA 20

28 163 2745 351 NA 7655 NA NA NA 21

37 303 449 5014 NA NA NA NA NA 22

5 43 823 >10000 >10000 10772 6784 NA NA 23

10 32 2860 3223 NA 4889 NA NA NA 24

2.4 44 9870 1422 NA >10000 7428 NA 7280 NA 25

9 155 13026 1836 NA NA NA 13514 180 NA 26

7 151 6496 967 NA 3018 100 342 43 NA 27

54 497 15973 908 NA 3257 NA NA NA NA 28

20 274 3719 1678 NA 4341 1718 NA NA NA 29

139 568 7676 2385 NA 83 943 NA NA NA 30

24 603 1173 5062 NA NA NA NA NA NA 31

>10000 NA 1741 32

3 122 >10000 1324 NA 572 1994 234 902 NA 33

72 620 7253 NA 132 1262 948 437 NA 34

2.4 172 >10000 1105 NA 3380 387 1954 691 NA 35

3354 4324 >10000 >10000 NA 1770 NA 280 1103 NA 36

1.4 31 7719 1090 NA NA NA NA 3019 NA 37

27 50 >10000 1099 NA NA NA 366 922 >10000 38

1.5 25 >10000 606 NA NA NA 1639 444 497 39

0.7 11 >10000 281 NA NA NA NA NA >10000 40

0.7 2 5893 491 NA NA NA NA NA NA 41

1.3 16 >10000 1707 NA NA NA NA NA 2314 42

18 1498 NA >10000 43

5 993 NA >10000 NA NA NA NA NA NA 44

66 2726 NA >10000 NA NA NA NA NA NA 45

47 904 NA 5281 NA NA NA NA NA NA 46

531 119 2355 NA 2653 NA NA 2283 NA >10000 NA 47

124 5289 NA >10000 NA NA NA NA NA NA 48

41 291 >10000 14695 NA NA NA NA 2694 NA 49

14 207 NA >10000 NA NA NA NA >10000 NA 50

68 826 NA 1127 NA NA 2865 NA NA NA 51

39 772 NA >10000 NA 4942 6706 5915 3506 NA 52

58 951 >10000 >10000 NA NA 956 NA NA NA 53

496 1748 NA 1851 NA 2857 NA NA NA NA 57

142 23 195 NA 1661 NA NA NA NA NA NA 58

6.5 129 NA 2831 NA 774 544 NA NA NA 59

108 1.2 139 NA 3003 NA 968 246 919 405 >10000 60

1 86 6974 1440 NA 2425 211 383 182 NA 61

128 3906 >10000 NA NA 5320 427 137 NA 62

18 161 >10000 NA 2891 1899 NA NA NA 63

ND 1987 >10000 NA 2067 660 NA NA NA 64

6.5 65 7448 381 NA 833 >10000 NA >10000 65

2 64 10632 497 NA 3925 >10000 NA >10000 66

EXAMPLE 1(Z)-7-((1R,5S)-2-Oxo-5-phenoxymethyl-cyclopent-3-enyl)-hept-5-enoic acidmethyl ester (6a, FIG. 1)

Step 1: Mitsonobu Reaction of Phenol and 1 to Give 2a.

A solution of diisopropyl azodicarboxylate (DIAD, 194 μL, 1.0 mmol) inTHF (1.5 mL) was added to a solution of alcohol 1 (441 mg, 1.0 mmol),triphenylphosphine (262 mg, 1.0 mmol) and phenol (94 mg, 1.0 mmol) inTHF (3.0 mL). After stirring 18 h at room temperature, the solvent wasremoved under a stream of nitrogen and the residue was suspended in Et₂O(50 mL). The mixture was washed with saturated aqueous NaHCO₃ (3×20 mL)and brine (20 mL) then the organic phase was dried (Na₂SO₄) filtered andconcentrated in vacuo. Purification of the residue by flash columnchromatography on silica gel (hexane→50% EtOAc/hexane, gradient)afforded 218 mg of the desired ether 2a contaminated with phenol(approximately 15% phenol by ¹H NMR analysis) which was taken on withoutfurther purification.

Step 2: Deprotection of 2a to Give 3a.

Pyridiniump-toluenesulfonate (PPTs, 9 mg, 0.036 mmol) was added to asolution of impure 2a (218 mg, ˜0.36 mmol) in methanol (3.6 mL) at roomtemperature under nitrogen. The solution was heated at 50° C. for 4 h,then cooled and concentrated in vacuo. Purification of the crude residueby flash column chromatography on silica gel (60% EtOAc/hexane→EtOAc,gradient) afforded 112 mg (32% over two steps) of diol 3a.

Step 3: Silylation of 3a to Give 4a.

Triethylamine (67 μL, 0.48 mmol), dimethylaminopyridine (8 mg, 0.065mmol), and tert-butyldimethylsilyl chloride (54 mg, 0.36 mmol) weresequentially added to a solution of 3a (112 mg, 0.32 mmol) in CH₂Cl₂(1.6 mL). The resulting solution was stirred at room temperature undernitrogen for 18 h. The reaction mixture was then concentrated in vacuo,then saturated aqueous NH₄Cl (20 mL) was added and the mixture wasextracted with EtOAc (3×30 mL). The combined organic extracts werewashed with brine (20 mL), dried (Na₂SO₄), filtered and concentrated invacuo. Purification of the crude residue by flash column chromatographyon silica gel (25%→60% EtOAc/hexane→EtOAc, gradient) afforded 96 mg(65%) of desired product 4a.

Step 4: Oxidation of 4a to Give 5a.

4-Methylmorpholine N-oxide (17.5 mg, 0.15 mmol) and 4 Å molecular sieves(25 mg) were added to a solution of 4a (46 mg, 0.10 mmol) in CH₂Cl₂ (0.5mL). The mixture was cooled to 0° C. and tetrapropylammoniumperruthenate (TPAP, 1.8 mg, 0.005 mmol) was added in one portion. Thereaction mixture was allowed to warm to room temperature. After 18 h atroom temperature the reaction was concentrated in vacuo. Purification ofthe crude residue by flash column chromatography on silica gel (15%→60%EtOAc/hexane) afforded 27 mg (59%) of 5a and 6 mg (18%) of the titlecompound (6a).

EXAMPLE 2(Z)-7-((1R,2S,3R)-3-Hydroxy-5-oxo-2-phenoxymethyl-cyclopentyl)-hept-5-enoicacid methyl ester (7a, FIG. 1)

HF-pyridine (100 μL) was added to a solution of 5a (27 mg, 0.059 mmol)in CH₃CN (1.2 mL) in a plastic scintillation vial at room temperature.After 18 h, the reaction was quenched with saturated aqueous NaHCO₃ (10mL) and extracted with EtOAc (3×15 mL). The combined organic extractswere dried (Na₂SO₄), filtered and concentrated in vacuo. Purification ofthe crude residue by flash column chromatography on silica gel (40%EtOAc/hexane) afforded 9 mg (44%) of the title compound (7a) and 4 mg(21%) of 6a.

EXAMPLE 3 AND EXAMPLE 4(Z)-7-((1R,5S)-2-Oxo-5-phenoxymethyl-cyclopent-3-enyl)-hept-5-enoic acid(8a) and(Z)-7-((1R,2S,3R)-3-Hydroxy-5-oxo-2-phenoxymethyl-cyclopentyl)-hept-5-enoicacid (9a)

Rabbit liver esterase (134 units/mg, 1 mg) was added to a solution of 6a(5.0 mg, 0.022 mmol) in MeCN (0.1 mL) and pH 7.2 buffer (0.72 mL). Afterstirring at room temperature for 18 h, the reaction mixture was dilutedwith MeCN (5 mL) and concentrated to dryness. The residue was suspendedin CH₂Cl₂, filtered through celite and concentrated. Purification of theresulting crude residue by flash column chromatography on silica gel(70% EtOAc/hexane→EtOAc→2% MeOH/EtOAc, gradient) afforded 0.9 mg (20%)of title compound 8a and 3.0 mg (63%) of title compound 9a.

EXAMPLE 5 7-((1R,5S)-2-Oxo-5-phenoxymethyl-cyclopentyl)-heptanoic acidmethyl ester (10a, FIG. 2)

Palladium on carbon (10 wt. %, 3 mg) was added to a solution of 6a (9.0mg, 0.027 mmol) in EtOAc (0.65 mL). A hydrogen atmosphere wasestablished by evacuating and refilling with hydrogen (3×) and thereaction mixture was stirred under a balloon of hydrogen for 18 h. Thereaction mixture was filtered through celite, washing with EtOAc, andthe filtrate was concentrated in vacuo to afford 7.5 mg (82%) of thetitle compound (10a).

EXAMPLE 6 7-((1R,5S)-2-Oxo-5-phenoxymethyl-cyclopentyl)-heptanoic acid(11a, FIG. 2)

The product of example 5 (10a, 6.5 mg, 0.020 mmol) was converted to thetitle compound (11a, 4.0 mg (64%)) in accordance with the procedure inExamples 3 and 4.

EXAMPLE 7(Z)-7-((1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-phenoxymethyl-cyclopentyl)-hept-5-enoicacid methyl ester (14a, FIG. 3)

Step 1: Mesylation of 4a to Give 12a.

Triethylamine (23 μL, 0.17 mmol) and methanesulfonyl chloride (11 μL,0.14 mmol) were added sequentially to a solution of 4a (51 mg, 0.11mmol) in CH₂Cl₂ (0.8 mL) at room temperature. After 18 h at roomtemperature, saturated aqueous NaHCO₃ (5 mL) was added and the mixturewas extracted with EtOAc (3×10 mL). The combined organic extracts weredried (Na₂SO₄), filtered and concentrated in vacuo. Purification of thecrude residue by flash column chromatography on silica gel (25%EtOAc/hexane) afforded 47 mg (79%) of 12a.

Step 2: Conversion of 12a to Chloride 13a.

Tetrabutylammonium chloride (250 mg, 0.90 mmol) was added to a solutionof 12a (47 mg, 0.087 mmol) in toluene (2.9 mL). The reaction mixture washeated at 50° C. for 18 h. The cooled mixture was diluted with brine (10mL) and extracted with EtOAc (3×25 mL). The combined organic extractswere dried (Na₂SO₄), filtered and concentrated in vacuo. Purification ofthe crude residue by flash column chromatography on silica gel (15%EtOAc/hexane) afforded 32 mg (77%) of 13a.

Step 3. Deprotection of 13a to Give 14a.

HF-pyridine (100 μL) was added to a solution of 13a (27 mg, 0.059 mmol)in CH₃CN (1.3 mL) in a plastic scintillation vial at room temperature.After 18 h, the reaction was quenched with saturated aqueous NaHCO₃ (10mL) and extracted with EtOAc (3×15 mL). The combined organic extractswere dried (Na₂SO₄), filtered and concentrated in vacuo. Purification ofthe crude residue by flash column chromatography on silica gel (25%EtOAc/hexane) afforded 20 mg (82%) of the title compound (14a).

EXAMPLE 8(Z)-7-((1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-phenoxymethyl-cyclopentyl)-hept-5-enoicacid (15a, FIG. 3)

The product of example 7 (14a, 6.0 mg, 0.020 mmol) was converted to thetitle compound (15a, 2.5 mg (44%)) in accordance with the procedure inExamples 3 and 4.

EXAMPLE 97-((1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-phenoxymethyl-cyclopentyl)-heptanoicacid methyl ester (16a, FIG. 4)

Palladium on carbon (10 wt. %, 3 mg) was added to a solution of 14a (9.0mg, 0.027 mmol) in EtOAc (0.7 mL). A hydrogen atmosphere was establishedby evacuating and refilling with hydrogen (5×) and the reaction mixturewas stirred under a balloon of hydrogen for 18 h. The reaction mixturewas filtered through celite, washing with EtOAc, and the filtrate wasconcentrated in vacuo to afford 9.0 mg (quant.) of the title compound(16a).

EXAMPLE 107-((1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-phenoxymethyl-cyclopentyl)-heptanoicacid (17a, FIG. 4)

The product of example 9 (16a, 8.0 mg, 0.021 mmol) was converted to thetitle compound (17a, 2.0 mg (26%)) in accordance with the procedure inExamples 3 and 4.

EXAMPLE 11(Z)-7-[(1R,2S,3R,5R)-5-Chloro-2-(3,5-dichloro-phenoxymethyl)-3-hydroxy-cyclopentyl]-hept-5-enoicacid methyl ester (14a, FIG. 3 [see also FIG. 1])

Step 1: Mitsonobu Reaction of 3,5-dichlorophenol and 1 to Give 2b.

Diisopropyl azodicarboxylate (DIAD, 342 μL, 1.76 mmol) was added to asolution of alcohol 1 (676 mg, 1.53 mmol), triphenylphosphine (613 mg,2.34 mmol) and 3,5-dichlorophenol (281 mg, 1.72 mmol) in THF (7.6 mL).After stirring 64 h at room temperature, the solvent was removed under astream of nitrogen. The residue was diluted with EtOAc (75 mL) and thenwashed with saturated aqueous NaHCO₃ (3×30 mL) and brine (30 mL) thenthe organic phase was dried (Na₂SO₄) filtered and concentrated in vacuo.Purification of the residue by flash column chromatography on silica gel(15% EtOAc/hexane) afforded 627 mg of the desired ether 2b contaminatedwith 3,5-dichlorophenol (approximately 14% phenol by ¹H NMR analysis)which was taken on without further purification.

Step 2: Deprotection of 2b to Give 3b.

Pyridinium p-toluenesulfonate (PPTs, 23 mg, 0.092 mmol) was added to asolution of impure 2b (627 mg, ˜0.92 mmol) in methanol (9.2 mL) at roomtemperature under nitrogen. The solution was heated at 50° C. for 16 h,then cooled and concentrated in vacuo. Purification of the crude residueby flash column chromatography on silica gel (65% EtOAc/hexane→EtOAc,gradient) afforded 220 mg (34% over two steps) of diol 3b.

Step 3: Silylation of 3b to Give 4b.

Triethylamine (110 μL, 0.79 mmol), dimethylaminopyridine (13 mg, 0.11mmol), and tert-butyldimethylsilyl chloride (88 mg, 0.58 mmol) weresequentially added to a solution of 3b (220 mg, 0.53 mmol) in CH₂Cl₂(2.6 mL). The resulting solution was stirred at room temperature undernitrogen for 18 h. The reaction mixture was then concentrated under astream of nitrogen, then saturated aqueous NH₄Cl (30 mL) was added andthe mixture was extracted with EtOAc (3×50 mL). The combined organicextracts were washed with brine (25 mL), dried (Na₂SO₄), filtered andconcentrated in vacuo. Purification of the crude residue by flash columnchromatography on silica gel (15%→70% EtOAc/hexane→EtOAc, gradient)afforded 163 mg (58%) of 4b.

Step 4: Mesylation of 4b to Give 12b.

Triethylamine (31 μL, 0.22 mmol) and methanesulfonyl chloride (15 μL,0.19 mmol) were added sequentially to a solution of 4b (80 mg, 0.15mmol) in CH₂Cl₂ (1.1 mL) at room temperature. After 18 h at roomtemperature, saturated aqueous NaHCO₃ (10 mL) was added and the mixturewas extracted with EtOAc (3×20 mL). The combined organic extracts weredried (Na₂SO₄), filtered and concentrated in vacuo. Purification of thecrude residue by flash column chromatography on silica gel (15%EtOAc/hexane) afforded 53 mg (58%) of 12b.

Step 5: Conversion of 12b to Chloride 13b and 14b.

Tetrabutylammonium chloride (250 mg, 0.90 mmol) was added to a solutionof 12b (53 mg, 0.087 mmol) in toluene (2.9 mL). The reaction mixture washeated at 50° C. for 18 h. The cooled mixture was diluted with brine (10mL) and extracted with EtOAc (3×25 mL). The combined organic extractswere dried (Na₂SO₄), filtered and concentrated in vacuo. Purification ofthe crude residue by flash column chromatography on silica gel (10%→50%EtOAc/hexane, gradient) afforded 33 mg (69%) of 13b and 10 mg (26%) ofthe title compound (14b).

Step 6. Deprotection of 13b to Give 14b.

HF-pyridine (100 μL) was added to a solution of 13a (33 mg, 0.060 mmol)in CH₃CN (1.2 mL) in a plastic scintillation vial at room temperature.After 18 h, the reaction was quenched with saturated aqueous NaHCO₃ (10mL) and extracted with EtOAc (3×15 mL). The combined organic extractswere dried (Na₂SO₄), filtered and concentrated in vacuo. Purification ofthe crude residue by flash column chromatography on silica gel (25%EtOAc/hexane) afforded 25 mg (96%) of the title compound (14b).

EXAMPLE 12(Z)-7-[(1R,2S,3R,5R)-5-Chloro-2-(3,5-dichloro-phenoxymethyl)-3-hydroxy-cyclopentyl]-hept-5-enoicacid (15b, FIG. 3)

The product of example 11 (14b, 10 mg, 0.023 mmol) was converted to thetitle compound (15b, 3.0 mg (31%)) in accordance with the procedure inExamples 3 and 4.

EXAMPLE 137-[(1R,2S,3R,5R)-5-Chloro-2-(3,5-dichloro-phenoxymethyl)-3-hydroxy-cyclopentyl]-heptanoicacid methyl ester (16b, FIG. 4)

Palladium on carbon (10 wt. %, 3 mg) was added to a solution of 14b (9.0mg, 0.027 mmol) in EtOAc (0.5 mL). A hydrogen atmosphere was establishedby evacuating and refilling with hydrogen (5×) and the reaction mixturewas stirred under a balloon of hydrogen for 18 h. The reaction mixturewas filtered through celite, washing with EtOAc, and the filtrate wasconcentrated in vacuo. Purification of the crude residue by flash columnchromatography on silica gel (15% EtOAc/hexane) afforded 2.5 mg (28%) ofthe title compound (16b).

EXAMPLE 147-[(1R,2S,3R,5R)-5-Chloro-2-(3,5-dichloro-phenoxymethyl)-3-hydroxy-cyclopentyl]-heptanoicacid (17b, FIG. 4)

The product of example 13 (16b, 2.0 mg, 0.005 mmol) was converted to thetitle compound (17b, 0.6 mg (31%)) in accordance with the procedure inExamples 3 and 4.

Preparation 1(Z)-7-[(1R,2S,3R,5R)-5-Chloro-2-hydroxymethyl-3-(tetrahydro-pyran-2-yloxy)-cyclopentyl]-hept-5-enoicacid allyl ester (21, FIG. 5)

Step 1: Mesylation of 18 to Give 19

Triethylamine (4.2 mL, 30 mmol) and methanesulfonyl chloride (1.9 mL, 24mmol) were added sequentially to a solution of(Z)-7-[(1R,2S,3R,5S)-2-(tert-butyl-dimethyl-silanyloxymethyl)-5-hydroxy-3-(tetrahydro-pyran-2-yloxy)-cyclopentyl]-hept-5-enoicacid allyl ester (18, 9.94 g, 20 mmol) in CH₂Cl₂ (150 mL) at 0° C. Thereaction mixture was allowed to warm to rt. After 18 h at rt, thereaction mixture was added to saturated aqueous NaHCO₃ (200 mL) andCH₂Cl₂ was removed in vacuo. The resulting aqueous mixture was extractedwith EtOAc (3×300 mL). The combined extracts were washed with brine (100mL), dried (Na₂SO₄), filtered and concentrated in vacuo to afford 11.5 g(quant.) of mesylate 19 as a pale yellow oil.

Step 2: Conversion of 19 to Chlorides 20 and 21

A mixture of 19 (1.73 g, 3.01 mmol) and tetrabutylammonium chloride (8.4g, 30.2 mmol) in toluene (100 mL) was stirred at 50° C. After 18 h, thereaction was cooled to rt and brine (150 mL) was added. The mixture wasextracted with EtOAc (3×200 mL). The combined extracts were washed withbrine (150 mL), dried (Na₂SO₄), filtered and concentrated in vacuo.Purification of the crude residue by flash column chromatography onsilica gel (10%→25%→50% EtOAc/hexane, gradient) afforded 695 mg (45%) ofchloride 20 along with 223 mg (18%) of the title compound (21).

Step 3: Deprotection of 20 to Give 21

Tetrabutylammonium fluoride (4.0 mL of a 1.0 M THF solution, 4.0 mmol)was added to a solution of 20 (695 mg, 1.35 mmol) in THF (5.4 mL) at 0°C. under N₂. The reaction mixture was allowed to warm to rt. After 18 hat rt, THF was removed under a stream of N₂. EtOAc (100 mL) was addedand the resulting mixture was washed with H₂O (2×50 mL) and brine (50mL) then dried (Na₂SO₄), filtered and concentrated in vacuo.Purification of the crude residue by flash column chromatography onsilica gel (30% EtOAc/hexane) afforded 392 mg (72%) of the titlecompound (21) as a colorless oil.

EXAMPLE 15(Z)-7-[(1R,2S,3R,5R)-2-(3,5-Bis-trifluoromethyl-phenoxymethyl)-5-chloro-3-hydroxy-cyclopentyl]-hept-5-enoicacid (15c, FIG. 6)

Step 1: Mitsunobu Reaction of 21 and Hydroxyaryl to Give 22c.

DIAD (50 μL, 0.26 mmol) was added to a solution of alcohol 21 (88 mg,0.22 mmol), triphenylphosphine (88 mg, 0.34 mmol) and3,5-bis(trifluoromethyl)phenol (40 μL, 0.26 mmol) in CH₂Cl₂ (1.1 mL).After stirring overnight at rt, the solvent was removed under a streamof nitrogen. The residue was diluted with EtOAc (25 mL), washed withsaturated aqueous NaHCO₃ (3×10 mL) and brine (10 mL) then the organicphase was dried (Na₂SO₄) filtered and concentrated in vacuo.Purification of the residue by flash column chromatography on silica gel(10% EtOAc/hexane) afforded 112 mg (83%) of the desired ether 22c.

Step 2: Deprotection of 22c to Give 23c.

Pyridiniump-toluenesulfonate (PPTs, 5 mg, 0.019 mmol) was added to asolution of 22c (112 mg, 0.18 mmol) in methanol (1.8 mL) at rt undernitrogen. The solution was heated at 50° C. overnight, then cooled andconcentrated in vacuo. Purification of the crude residue by flash columnchromatography on silica gel (25% EtOAc/hexane→EtOAc, gradient) afforded24 mg (25%) of pure 22c and 67 mg (70%) of 22c contaminated with 10% ofa slightly more polar impurity.

Step 3: Saponification of 22c to Give 15c.

Lithium hydroxide (0.05 mL of a 1.0 M aqueous solution, 0.05 mmol) wasadded to a solution of ester 22c (9 mg, 0.017 mmol) in THF (0.17 mL).After stirring overnight at rt, the solvent was removed under a streamof nitrogen. H₂O (2 mL) was added, the mixture was acidified with 1.0 Maqueous HCl (0.5 mL), and the resulting cloudy solution was extractedwith EtOAc (3×10 mL). The combined extracts were washed with brine (10mL), dried (Na₂SO₄), filtered and concentrated in vacuo to afford 8 mg(96%) of the title compound (15c).

EXAMPLE 16(Z)-7-[(1R,2S,3R,5R)-2-(3,5-Bis-trifluoromethyl-phenoxymethyl)-5-chloro-3-hydroxy-cyclopentyl]-heptanoicacid (17c, FIG. 7)

Step 1: Hydrogenation of 23c to Give 24c.

Palladium on carbon (10 wt. %, 3 mg) was added to a solution of 23c (12mg, 0.023 mmol) in EtOAc (0.5 mL). A hydrogen atmosphere was establishedby evacuating and refilling with hydrogen (5×) and the reaction mixturewas stirred under a balloon of hydrogen for 4 h. The reaction mixturewas filtered through celite, washing with EtOAc, and the filtrate wasconcentrated in vacuo to afford 12 mg (99%) of propyl ester 24c.

Step 2: Saponification of 24c to Give 17c.

Lithium hydroxide (0.1 mL of a 1.0 M aqueous solution, 0.1 mmol) wasadded to a solution of ester 24c (10 mg, 0.019 mmol) in THF (0.19 mL).The mixture was heated at 40° C. for 3 h, then cooled and the solventwas removed under a stream of nitrogen. H₂O (2 mL) was added, themixture was acidified with 1.0 M aqueous HC; (0.5 mL), and the resultingcloudy solution was extracted with EtOAc (3×10 mL). The combinedextracts were washed with brine (10 mL), dried (Na₂SO₄), filtered andconcentrated in vacuo. Purification of the crude residue by flash columnchromatography on silica gel (25%→50% EtOAc/hexane, gradient) afforded8.5 mg (85%) starting material 24c and 1.3 mg (14%) of the titlecompound (17c).

EXAMPLE 17(Z)-7-[(1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-(naphthalen-2-yloxymethyl)-cyclopentyl]-hept-5-enoicacid (15d)

Alcohol 21 (86 mg, 0.21 mmol) and 2-naphthol (37 mg, 0.26 mmol) wereconverted into the title compound (15d) in accordance with theprocedures of Example 15.

EXAMPLE 18(Z)-7-[(1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-(naphthalen-2-yloxymethyl)-cyclopentyl]-heptanoicacid (17d)

Step 1: Hydrogenation of 23d to Give 24d.

Alkene 23d from Example 17, step 2 (21 mg, 0.047 mmol) was convertedinto 20 mg (94%) of propyl ester 24d in accordance with step 1 ofExample 16.

Step 2: Esterase Reaction of 24d to Give 17d.

Propyl ester 24d (19 mg, 0.043 mmol) was converted into 2 mg (12%) thetitle compound (17d) in accordance with the procedure in Examples 3 and4; 8 mg (42%) of the starting ester (24d) was also recovered.

EXAMPLE 19(Z)-7-[(1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-(naphthalen-1-yloxymethyl)-cyclopentyl]-hept-5-enoicacid (15e)

Alcohol 21 (51 mg, 0.13 mmol) and 1-naphthol (22 mg, 0.15 mmol) wereconverted into the title compound (15e) in accordance with theprocedures of Example 15.

EXAMPLE 20(Z)-7-[(1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-(naphthalen-1-yloxymethyl)-cyclopentyl]-heptanoicacid (17e)

Alkene 23e from Example 19, step 2 (16 mg, 0.036 mmol) was convertedinto the title compound (17e) in accordance with the procedures inExample 16; the second step was carried out at 40° C. for 20 h.

EXAMPLE 21(Z)-7-[(1R,2S,3R,5R)-5-Chloro-2-(2-chloro-phenoxymethyl)-3-hydroxy-cyclopentyl]-hept-5-enoicacid (15f)

Alcohol 21 (78 mg, 0.20 mmol) and 2-chlorophenol (23 μL, 0.23 mmol) wereconverted into the title compound (15f) in accordance with theprocedures of Example 15.

EXAMPLE 22(Z)-7-[(1R,2S,3R,5R)-5-Chloro-2-(3-chloro-phenoxymethyl)-3-hydroxy-cyclopentyl]-hept-5-enoicacid (15 g)

Alcohol 21 (78 mg, 0.20 mmol) and 3-chlorophenol (24 μL, 0.23 mmol) wereconverted into the title compound (15 g) in accordance with theprocedures of Example 15.

EXAMPLE 23(Z)-7-[(1R,2S,3R,5R)-5-Chloro-2-(4-chloro-phenoxymethyl)-3-hydroxy-cyclopentyl]-hept-5-enoicacid (15h)

Alcohol 21 (78 mg, 0.20 mmol) and 4-chlorophenol (29 mg, 0.23 mmol) wereconverted into the title compound (15h) in accordance with theprocedures of Example 15.

EXAMPLE 24(Z)-7-[(1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-(3-trifluoromethyl-phenoxymethyl)-cyclopentyl]-hept-5-enoicacid (15i)

Alcohol 21 (100 mg, 0.25 mmol) and 3-trifluoromethylphenol (36 μL, 0.30mmol) were converted into the title compound (15i) in accordance withthe procedures of Example 15.

EXAMPLE 25(Z)-7-((1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-m-tolyloxymethyl-cyclopentyl)-hept-5-enoicacid (15j)

Alcohol 21 (109 mg, 0.27 mmol) and m-cresol (36 μL, 0.33 mmol) wereconverted into the title compound (15j) in accordance with theprocedures of Example 15.

EXAMPLE 26(Z)-7-[(1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-(3-isopropyl-phenoxymethyl)-cyclopentyl]-hept-5-enoicacid (15k)

Alcohol 21 (105 mg, 0.26 mmol) and 3-isopropylphenol (43 μL, 0.31 mmol)were converted into the title compound (15k) in accordance with theprocedures of Example 15.

EXAMPLE 27(Z)-7-[(1R,2S,3R,5R)-2-(3-tert-Butyl-phenoxymethyl)-5-chloro-3-hydroxy-cyclopentyl]-hept-5-enoicacid (151)

Alcohol 21 (121 mg, 0.30 mmol) and 3-tert-butylphenol (54 mg, 0.36 mmol)were converted into the title compound (151) in accordance with theprocedures of Example 15.

EXAMPLE 28(Z)-7-[(1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-(3-methoxy-phenoxymethyl)-cyclopentyl]-hept-5-enoicacid (15m)

Alcohol 21 (104 mg, 0.26 mmol) and 3-methoxyphenol (34 μL, 0.31 mmol)were converted into the title compound (15m) in accordance with theprocedures of Example 15.

EXAMPLE 293-[(1S,2R,3R,5R)-2-((Z)-6-carboxy-hex-2-enyl)-3-chloro-5-hydroxy-cyclopentylmethoxy]-phenylbenzoate (15n, FIG. 8)

Step 1 and 2: Mitsunobu Reaction and THP Deprotection to Give 23n.

Alcohol 21 (70 mg, 0.18 mmol) and monobenzoyl resorcinol (43 mg, 0.20mmol) were converted into benzoate 23n in accordance with the proceduresof Example 15, steps 1 and 2.

Step 3: Deallylation of 23n to Give 15n.

Tetrakis(triphenylphosphine)palladium(0) (2 mg, 0.0017 mmol) was addedto a solution of allyl ester 23n (17.5 mg, 0.034 mmol) in CH₂Cl₂ (0.34mL). The reaction mixture was cooled to 0° C. and pyrrolidine (3.1 mL,0.037 mmol) was added. After 15 min at 0° C. the solvent was removedunder a stream of nitrogen. H₂O (2 mL) and 1.0 M aqueous HCl (1 mL) wereadded and the mixture was extracted with EtOAc (3×10 mL). The combinedextracts were washed with brine (10 mL), dried (Na₂SO₄), filtered andconcentrated in vacuo. Purification of the crude residue by flash columnchromatography on silica gel (60%→80% EtOAc/hexane→EtOAc→10% MeOH/EtOAc,gradient) afforded 1.7 mg (11%) of the title compound (15n).

EXAMPLE 30(Z)-7-[(1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-(3-hydroxy-phenoxymethyl)-cyclopentyl]-hept-5-enoicacid (15o, FIG. 8)

Ester 23n from Example 29, step 2 was converted to the title compound(15o) in accordance with the procedure of Example 15, step 3.

EXAMPLE 31(Z)-7-{(1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-[4-(1-methyl-1-phenyl-ethyl)-phenoxymethyl]-cyclopentyl}-hept-5-enoicacid (15p)

Alcohol 21 (130 mg, 0.32 mmol) and 4-cumylphenol (83 mg, 0.39 mmol) wereconverted into the title compound (15p) in accordance with theprocedures of Example 15.

EXAMPLE 32(Z)-7-[(1R,2S,3R,5R)-5-Chloro-2-(2,3-dimethyl-phenoxymethyl)-3-hydroxy-cyclopentyl]-hept-5-enoicacid (15q)

Alcohol 21 (153 mg, 0.38 mmol) and 2,3-dimethylphenol (56 mg, 0.46 mmol)were converted into the title compound (15q) in accordance with theprocedures of Example 15.

EXAMPLE 33(Z)-7-[(1R,2S,3R,5R)-5-Chloro-2-(2,4-dimethyl-phenoxymethyl)-3-hydroxy-cyclopentyl]-hept-5-enoicacid (15r)

Alcohol 21 (117 mg, 0.29 mmol) and 2,4-dimethylphenol (42 μL, 0.35 mmol)were converted into the title compound (15r) in accordance with theprocedures of Example 15.

EXAMPLE 34

(Z)-7-[(1R,2S,3R,5R)-5-Chloro-2-(2,5-dimethyl-phenoxymethyl)-3-hydroxy-cyclopentyl]-hept-5-enoicacid (15s)

Alcohol 21 (118 mg, 0.29 mmol) and 2,5-dimethylphenol (43 mg, 0.35 mmol)were converted into the title compound (15s) in accordance with theprocedures of Example 15.

EXAMPLE 35(Z)-7-[(1R,2S,3R,5R)-5-Chloro-2-(2,6-dimethyl-phenoxymethyl)-3-hydroxy-cyclopentyl]-hept-5-enoicacid (15t)

Alcohol 21 (131 mg, 0.33 mmol) and 2,6-dimethyl phenol (50 mg, 0.41mmol) were converted into the title compound (15t) in accordance withthe procedures of Example 15.

EXAMPLE 36(Z)-7-[(1R,2S,3R,5R)-5-Chloro-2-(3,5-dimethyl-phenoxymethyl)-3-hydroxy-cyclopentyl]-hept-5-enoicacid (15u)

Alcohol 21 (112 mg, 0.28 mmol) and 3,5-dimethylphenol (41 mg, 0.34 mmol)were converted into the title compound (15u) in accordance with theprocedures of Example 15.

EXAMPLE 37(Z)-7-[(1R,2S,3R,5R)-5-Chloro-2-(3,4-dimethyl-phenoxymethyl)-3-hydroxy-cyclopentyl]-hept-5-enoicacid (15v)

Alcohol 21 (150 mg, 0.37 mmol) and 3,4-dimethylphenol (55 mg, 0.45 mmol)were converted into the title compound (15v) in accordance with theprocedures of Example 15.

EXAMPLE 38(Z)-7-[(1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-(3,4,5-trimethyl-phenoxymethyl)-cyclopentyl]-hept-5-enoicacid (15w)

Alcohol 21 (70 mg, 0.18 mmol) and 3,4,5-trimethylphenol (28 mg, 0.21mmol) were converted into the title compound (15w) in accordance withthe procedures of Example 15.

EXAMPLE 39(Z)-7-[(1R,2S,3R,5R)-5-Chloro-2-(4-chloro-3,5-dimethyl-phenoxymethyl)-3-hydroxy-cyclopentyl]-hept-5-enoicacid (15×)

Alcohol 21 (33 mg, 0.082 mmol) and 4-chloro-3,5-dimethylphenol (15 mg,0.096 mmol) were converted into the title compound (15×) in accordancewith the procedures of Example 15.

EXAMPLE 40(Z)-7-[(1R,2S,3R,5R)-5-Chloro-2-(4-chloro-naphthalen-1-yloxymethyl)-3-hydroxy-cyclopentyl]-hept-5-enoicacid (15y)

Alcohol 21 (78 mg, 0.20 mmol) and 4-chloro-1-naphthnol (40 mg, 0.22mmol) were converted into the title compound (15y) in accordance withthe procedures of Example 15.

EXAMPLE 41(Z)-7-[(1R,2S,3R,5R)-5-Chloro-2-(3-chloro-2-fluoro-5-trifluoromethyl-phenoxymethyl)-3-hydroxy-cyclopentyl]-hept-5-enoicacid (15z)

Alcohol 21 (78 mg, 0.20 mmol) and3-chloro-2-fluoro-5-trifluoromethylphenol (49 mg, 0.23 mmol) wereconverted into the title compound (15z) in accordance with theprocedures of Example 15.

EXAMPLE 42(Z)-7-[(1R,2S,3R,5R)-5-Chloro-2-(4-formyl-phenoxymethyl)-3-hydroxy-cyclopentyl]-hept-5-enoicacid (15aa)

Alcohol 21 (155 mg, 0.39 mmol) and 4-hydroxybenzaldehyde (55 mg, 0.45mmol) were converted into the title compound (15aa) in accordance withthe procedures of Example 15.

EXAMPLE 43(Z)-7-[(1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-(4-hydroxymethyl-phenoxymethyl)-cyclopentyl]-hept-5-enoicacid (15bb, FIG. 9)

Step 1: Reduction of Aldehyde 22aa to Alcohol 22bb

Sodium borohydride (1.8 mg, 0.048 mmol) and methanol (0.05 mL) wereadded sequentially to a solution of aldehyde 22aa from Example 42, step1 (25 mg, 0.048 mmol) at 0° C. After 5 min at 0° C., the reaction wasquenched by addition of 1.0 M aqueous HCl (0.5 mL). The mixture wasdiluted with H₂O and extracted with EtOAc (3×10 mL). The combinedextracts were dried (Na₂SO₄), filtered and concentrated in vacuo.Purification of the crude residue by flash column chromatography onsilica gel (30% EtOAc/hexane) afforded 15 mg (60%) of alcohol 22bb.

Step 2: Deprotection of 22bb to Give 23bb

Alcohol 22bb (15 mg, 0.030 mmol) was converted into 10 mg (80%) of diol23bb in accordance with the procedure of Example 15, step 2.

Step 3: Saponification of 23bb to Give 15bb.

Diol ester 23bb (10 mg, 0.024 mmol) was converted into 9 mg (99%) of thetitle compound (15bb) in accordance with the procedure of Example 15,step 3.

EXAMPLE 44(Z)-7-{(1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-[4-(1-hydroxy-butyl)-phenoxymethyl]-cyclopentyl}-hept-5-enoicacid (15cc, FIGS. 9 and 10)

Step 1: Grignard Addition to Aldehyde 22aa

n-Propylmagnesium chloride (2.0 M solution in Et₂O, 30 μL, 0.06 mmol)was added to a solution of aldehyde 22aa from Example 42, step 1 (30 mg,0.059 mmol) in THF (0.3 mL) at 0° C. under nitrogen. After 2 h at 0° C.,the reaction was quenched by the addition of saturated aqueous NH₄Cl (5mL) and THF was removed under a stream of nitrogen. The resultingmixture was extracted with EtOAc (3×15 mL). The combined extracts werewashed with brine (10 mL), dried (Na₂SO₄), filtered and concentrated invacuo to afford 32 mg (98%) of alcohol 22cc.

Step 2: Deprotection of 22cc to give 23cc and 23dd

Ether 22cc (32 mg, 0.058 mmol) was converted to 4 mg (15%) of diol 23ccand 20 mg (72%) of methyl ether 23dd in accordance with the procedure ofExample 15, step 2.

Step 3: Saponification of 23cc to Give 15cc

Ester 23cc (4 mg, 0.009 mmol) was converted into 3 mg (82%) of the titlecompound (15cc) in accordance with the procedure of Example 15, step 3.

EXAMPLE 45(Z)-7-{(1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-[4-(1-methoxy-butyl)-phenoxymethyl]-cyclopentyl}-hept-5-enoicacid (15dd, FIGS. 9 and 10)

Ester 23dd from Example 44, step 2 (10 mg, 0.021 mmol) was convertedinto 8.5 mg (92%) of the title compound (15dd) in accordance with theprocedure of Example 15, step 3.

EXAMPLE 46(Z)-7-{(1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-[4-(1-hydroxy-hexyl)-phenoxymethyl]-cyclopentyl}-hept-5-enoicacid (15ee, FIGS. 9 and 11)

Step 1: Grignard Addition to Aldehyde 22aa

Addition of pentylmagnesium bromide (2.0 M in Et₂O, 20 μL, 0.04 mmol) toaldehyde 22aa from Example 42, step 1 (19 mg, 0.038 mmol) was carriedout in accordance with the procedure of Example 44, step 1 to afford 5mg (23%) of alcohol 22ee.

Step 2: Deprotection of Alcohol 22ee to Give Diol 23ee

A mixture of acetic acid, THF and H₂O (4:2:1, 0.2 mL) was added toalcohol 22ee (5 mg, 0.009 mmol) and the resulting mixture was heated at40° C. overnight. After 18 h, the reaction was allowed to cool to rtthen toluene (5 mL) was added and the mixture was concentrated in vacuo.Purification of the crude residue by flash column chromatography onsilica gel (35% EtOAc/hexane) afforded 2 mg (47%) of diol 23ee.

Step 3: Saponification of 23ee to Give 15ee

Ester 23ee (3 mg, 0.004 mmol) was converted into 1.8 mg (98%) of thetitle compound (15ee) in accordance with the procedure of Example 15,step 3.

EXAMPLE 47(Z)-7-{(1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-[4-(1-hydroxy-ethyl)-phenoxymethyl]-cyclopentyl}-hept-5-enoicacid (15ff, FIGS. 9 and 11)

Methylmagnesium bromide (3.0 M in Et₂O, 20 μL, 0.06 mmol) and aldehyde22aa from Example 42, step 1 (22 mg, 0.044 mmol) were converted into thetitle compound (15ff) in accordance with the procedures of Example 46.

EXAMPLE 48(Z)-7-[(1R,2S,3R,5R)-5-Chloro-2-(3-formyl-phenoxymethyl)-3-hydroxy-cyclopentyl]-hept-5-enoicacid (15gg)

Alcohol 21 (206 mg, 0.51 mmol) and 3-hydroxybenzaldehyde (73 mg, 0.60mmol) were converted into the title compound (15gg) in accordance withthe procedures of Example 15.

EXAMPLE 49(Z)-7-[(1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-(3-hydroxymethyl-phenoxymethyl)-cyclopentyl]-hept-5-enoicacid (15hh, FIG. 9)

Aldehyde 22gg from Example 48, step 1 was converted to the titlecompound (15hh) in accordance with the procedures of Example 43.

EXAMPLE 50(Z)-7-{(1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-[3-(1-hydroxy-hexyl)-phenoxymethyl]-cyclopentyl}-hept-5-enoicacid (15ii, FIG. 9)

Step 1: Grignard Addition to Aldehyde 22gg

Addition of pentylmagnesium bromide (2.0 M in Et₂O, 32 μL, 0.064 mmol)to aldehyde 22gg from Example 48, step 1 (16 mg, 0.032 mmol) was carriedout in accordance with the procedure of Example 44, step 1 to afford 17mg (100%) of alcohol 22ii.

Step 2: Deprotection of Alcohol 22ii to Give Diol 23ii.

Ether 22ii (17 mg, 0.032 mmol) was converted to 11 mg (70%) of diol 23iiin accordance with the procedure of Example 15, step 2.

Step 3: Saponification of 23ii to give 15ii

Ester 23ii (11 mg, 0.022 mmol) was converted into 9 mg (89%) of thetitle compound (15ii) in accordance with the procedure of Example 15,step 3.

EXAMPLE 51(Z)-7-{(1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-[3-(1-hydroxy-2-methyl-propyl)-phenoxymethyl]-cyclopentyl}-hept-5-enoicacid (15jj, FIG. 9)

Isopropylmagnesium chloride (2.0 M in Et₂O, 30 μL, 0.06 mmol) andaldehyde 22gg from Example 48, step 1 (15.5 mg, 0.031 mmol) wereconverted into the title compound (15jj) in accordance with theprocedures of Example 50.

EXAMPLE 52(Z)-7-{(1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-[3-(1-hydroxy-butyl)-phenoxymethyl]-cyclopentyl}-hept-5-enoicacid (15kk, FIG. 9)

n-Propylmagnesium chloride (2.0 M in Et₂O, 30 μL, 0.06 mmol) andaldehyde 22gg from Example 48, step 1 (15.7 mg, 0.031 mmol) wereconverted into the title compound (15kk) in accordance with theprocedures of Example 50.

EXAMPLE 53(Z)-7-{(1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-[3-(1-hydroxy-2-phenyl-ethyl)-phenoxymethyl]-cyclopentyl}-hept-5-enoicacid (15ll, FIG. 9)

Benzylmagnesium chloride (2.0 M in THF, 35 μL, 0.07 mmol) and aldehyde22gg from Example 48, step 1 (17.5 mg, 0.035 mmol) were converted intothe title compound (15ll) in accordance with the procedures of Example50.

EXAMPLE 54(Z)-7-{(1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-[3-(1-hydroxy-ethyl)-phenoxymethyl]-cyclopentyl}-hept-5-enoicacid (15 mm, FIG. 9)

Methylmagnesium bromide (3.0 M in Et₂O, 21 μL, 0.063 mmol) and aldehyde22gg from Example 48, step 1 (15.7 mg, 0.031 mmol) were converted intothe title compound (15 mm) in accordance with the procedures of Example50.

EXAMPLE 55(Z)-7-[(1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-(2-hydroxymethyl-phenoxymethyl)-cyclopentyl]-hept-5-enoicacid (15nn)

Alcohol 21 (150 mg, 0.37 mmol) and2-(tert-butyldimethylsilanyloxymethyl)-phenol (see Ankala, S. V. andFenteany, G., Tetrahedron Lett. 2002, 43, 4729-4732, 104 mg, 0.43 mmol)were converted into the title compound (15nn) in accordance with theprocedures of Example 15.

EXAMPLE 56(Z)-7-[(1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-(4-hydroxymethyl-3,5-dimethyl-phenoxymethyl)-cyclopentyl]-hept-5-enoicacid (15 pp)

Step 1: Alcohol 21 (73 mg, 0.18 mmol) and2,6-dimethyl-4-hydroxybenzaldehyde (32 mg, 0.21 mmol) were convertedinto 53 mg (54%) of aldehyde 22oo in accordance with the procedure ofExample 15, step 1.

Step 2: Aldehyde 22oo (53 mg, 0.10 mmol) was converted into 53 mg(quant.) of alcohol 22 pp in accordance with the procedure of Example43, step 1.

Step 3: Alcohol 22 pp (24 mg, 0.045 mmol) was converted into 5 mg (52%)of diol 23 pp in accordance with the procedure of Example 46, step 2.

Step 4: Ester 23 pp (10 mg, 0.022 mmol) was converted into 5 mg (53%) ofthe title compound (15 pp) in accordance with the procedure of Example15, step 3.

EXAMPLE 57(Z)-7-[(1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-(4-methoxymethyl-3,5-dimethyl-phenoxymethyl)-cyclopentyl]-hept-5-enoicacid (15qq)

Step 1: Alcohol 22 pp from Example 56, step 2 (22 mg, 0.041 mmol) wasconverted into 10 mg (52%) of methyl ether 23qq xx in accordance withthe procedure of Example 15, step 2.

Step 2: Ester 23qq (10 mg, 0.022 mmol) was converted into 5 mg (53%) ofthe title compound (15qq) in accordance with the procedure of Example15, step 3.

EXAMPLE 58(Z)-7-[(1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-(1-oxo-indan-4-yloxymethyl)-cyclopentyl]-hept-5-enoicacid (15rr)

Alcohol 21 (100 mg, 0.25 mmol) and 4-hydroxyindanone (43 mg, 0.29 mmol)were converted into the title compound (15rr) in accordance with theprocedures of Example 15.

EXAMPLE 59(Z)-7-[(1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-(1-hydroxy-indan-4-yloxymethyl)-cyclopentyl]-hept-5-enoicacid (15ss)

Step 1: Ketone 22rr from example 58, step 1 (55 mg, 0.10 mmol) wasconverted into 11 mg (20%) of alcohol 22ss in accordance with theprocedure of Example 43, step 1; the reaction was carried out for 30min, and 35 mg (64%) of the starting ketone 22rr was also isolated.

Step 2: Ether 22ss (11 mg, 0.021 mmol) was converted into 5 mg (54%) ofdiol 23ss in accordance with the procedure of Example 15, step 2.

Step 3: Ester 23ss (5 mg, 0.01 mmol) was converted into 4 mg (88%) ofthe title compound (15ss) in accordance with the procedure of Example15, step 3.

EXAMPLE 60(Z)-7-[(1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-(5-hydroxy-5,6,7,8-tetrahydro-naphthalen-1-yloxymethyl)-cyclopentyl]-hept-5-enoicacid (15tt)

Alcohol 21 (127 mg, 0.32 mmol) and 5-hydroxy-1-tetralone (62 mg, 0.38mmol) were converted into the title compound (15tt) in accordance withthe procedures of Example 15 and Example 43, step 1; the reduction stepwas carried out after PPTs hydrolysis and before ester saponification.

EXAMPLE 61(Z)-7-{(1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-[2-(2-hydroxy-ethyl)-phenoxymethyl]-cyclopentyl}-hept-5-enoicacid (15uu)

Step 1: Bis-acylation of hydroxyphenol 25a to Give 26a (FIG. 12).

Triethylamine (0.63 mL, 4.5 mmol), dimethylaminopyridine (37 mg, 0.30mmol) and acetic anhydride (0.43 mL, 4.5 mmol) were added sequentiallyto a solution of 2-hydroxyphenethyl alcohol (25a, 417 mg, 3.0 mmol) inCH₂Cl₂ (6 mL). After stirring at rt overnight, the reaction was quenchedwith saturated aqueous NaHCO₃ and extracted with EtOAc (3×). Thecombined extracts were washed with H₂O and brine, dried (Na₂SO₄),filtered and concentrated in vacuo. Purification of the crude residue byflash column chromatography on silica gel (30% EtOAc/hexane) afforded355 mg (53%) of diacetate 26a.

Step 2: Mono-deacylation of 26a to Give 27a (FIG. 12).

Saturated aqueous NaHCO₃ (10 mL) was added to a solution of diacetate26a (355 mg, 1.60 mmol) in MeOH (4 mL) and the mixture was stirredovernight. After 24 h, the reaction was diluted with H₂O and extractedwith EtOAc (3×). Combined extracts were dried (MgSO₄), filtered andconcentrated in vacuo. Purification of the crude residue by flash columnchromatography on silica gel (35% EtOAc/hexane) afforded 90 mg (31%) ofphenol 27a.

Steps 3-5: Alcohol 21 (166 mg, 0.41 mmol) and phenol 27a (90 mg, 0.50mmol) were converted into the title compound (15uu) in accordance withthe procedures of Example 15.

EXAMPLE 62(Z)-7-{(1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-[3-(2-hydroxy-ethyl)-phenoxymethyl]-cyclopentyl}-hept-5-enoicacid (15vv)

2-(3-Hydroxyphenyl)ethanol (25b) was converted into the title compound(15vv) in accordance with the procedures of Example 61

EXAMPLE 63(Z)-7-{(1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-[4-(2-hydroxy-ethyl)-phenoxymethyl]-cyclopentyl}-hept-5-enoicacid (15ww)

Alcohol 21 (140 mg, 0.035 mmol) and 2-(4-hydroxyphenyl)-ethyl acetate(see Procopiou et al. J. Org. Chem. 1998, 63, 2342-2347, 76 mg, 0.42mmol) were converted into the title compound (15ww) in accordance withthe procedures of Example 15.

Preparation 2 3-chloro-5-hydroxybenzyl acetate (33, FIG. 13)

Step 1: Methylation of 28 to Give 29.

Concentrated sulfuric acid (0.04 mL, 0.48 mmol) was added to a solutionof 3-chloro-5-hydroxy-benzoic acid (28, 500 mg, 2.9 mmol) in MeOH (3.5mL) and the resulting solution was heated at reflux for 5.5 h. Thereaction was allowed to cool to rt then partitioned between saturatedaqueous NaHCO₃ (50 mL) and EtOAc (50 mL). The phases were separated andthe aqueous phase was extracted with EtOAc (2×20 mL). The combinedorganic phases were washed with brine (20 mL), dried (MgSO₄), filteredand concentrated in vacuo to afford 540 mg (99%) of ester 29.

Step 2: Silylation of 29 to Give 30.

Diisopropylethylamine (0.37 mL, 2.1 mmol) and tert-butyldimethylsilylchloride (250 mg, 1.7 mmol) were added to a solution of phenol 29 (280mg, 1.5 mmol) in DMF (1 mL) at 0° C. After 1 h, the reaction mixture waspoured into EtOAc (50 mL) and H₂O (25 mL). The layers were separated andthe organic phase was washed with H₂O (25 mL) and brine (20 mL), thendried (MgSO₄), filtered and concentrated in vacuo. Purification of thecrude residue by flash column chromatography on silica gel (hexane→5%EtOAc/hexane) afforded 449 mg (99%) of silyl ether 30.

Step 3: Reduction of Ester 30 to Alcohol 31

A solution of ester 30 (220 mg, 0.73 mmol) in THF (1 mL) was added viasyringe to a suspension of LiBH₄ (24 mg, 1.1 mmol) in THF (0.5 mL) at 0°C. The solution was heated at reflux. The reaction was cooled to rt andpoured into a mixture of ice and 10% acetic acid. The mixture wasextracted with EtOAc. The combined organic phase was washed with H₂O andbrine then dried (MgSO₄), filtered and concentrated in vacuo.Purification of the crude residue by flash column chromatography onsilica gel (10% EtOAc/hexane) afforded 149 mg (75%) of alcohol 31.

Step 4. Acylation of Alcohol 31 to Give Acetate 32.

Pyridine (49 μL, 0.61 mmol) and acetyl chloride (43 μl, 0.61 mmol) wereadded sequentially to a solution of alcohol 31 (150 mg, 0.55 mmol) inCH₂Cl₂ (1.0 mL). After 5 min, the reaction mixture was partitionedbetween saturated aqueous NaHCO₃ (10 mL) and CH₂Cl₂ (20 mL). The phaseswere separated and the aqueous phase was extracted with CH₂Cl₂ (2×15mL). The combined organic phases were washed with brine (10 mL), dried(MgSO₄), filtered and concentrated in vacuo. Purification of the cruderesidue by flash column chromatography on silica gel (10% EtOAc/hexane)afforded 135 mg (78%) of acetate 32.

Step 5: Disilylation of 32 to Give Phenol 33.

Tetrabutylammonium fluoride (1.0 M in THF, 1.28 mL, 1.28 mmol) was addedto a solution of silyl ether 32 (135 mg, 0.43 mmol) in THF (1.0 mL) andthe reaction was allowed to stir overnight at rt. The reaction was thenpartitioned between H₂O (10 mL) and EtOAc (20 mL). The layers wereseparated and the organic phase was washed with H₂O (2×15 mL) and brine(10 mL), then dried (MgSO₄), filtered and concentrated in vacuo.Purification of the crude residue by flash column chromatography onsilica gel (20% EtOAc/hexane) afforded 40 mg (56%) of the title compound(33).

EXAMPLE 64(Z)-7-[(1R,2S,3R,5R)-2-(3-Acetoxymethyl-5-chloro-phenoxymethyl)-5-chloro-3-hydroxy-cyclopentyl]-hept-5-enoicacid (15xx, FIG. 14)

Step 1: Alcohol 21 (80 mg, 0.20 mmol) and phenol 33 from Preparation 2(40 mg, 0.24 mmol) were converted into 70 mg (60%) of ether 22xx inaccordance with the procedure of Example 15, step 1

Step 2: Ester 22xx (70 mg, 0.12 mmol) was converted into 60 mg (impure,contaminated with PPh₃) of acid 34 in accordance with the procedure ofExample 29, step 3.

Step 3: Ether 34 (30 mg, 0.55 mmol) was converted into 5 mg (20%) of thetitle compound (15xx) in accordance with the procedure of Example 15,step 2

EXAMPLE 65(Z)-7-[(1R,2S,3R,5R)-5-Chloro-2-(3-chloro-5-hydroxymethyl-phenoxymethyl)-3-hydroxy-cyclopentyl]-hept-5-enoicacid (15yy)

Acetate 15xx from Example 64 (1.7 mg, 0.037 mmol) was converted into 1.3mg (84%) of the title compound (15yy) in accordance with the procedureof Example 15, step 3; the reaction time was 2 h.

Preparation 3 2-(4-hydroxy-2,6-dimethylphenyl)-ethyl acetate (41, FIG.15)

Step 1: Protection of Phenol 35 to Give Aldehyde 36

A solution of 4-methoxybenzyl chloride (0.22 mL, 1.6 mmol) in DMF (2 mL)was added to a mixture of 4-hydroxy-2,6-dimethylbenzaldehyde (35, 200mg, 1.33 mmol) and K₂CO₃ (460 mg, 3.32 mmol) in DMF (8 mL). The mixturewas heated at 100° C. for 2 h, then cooled to rt and partitioned betweensaturated aqueous H₂O (25 mL) and EtOAc (40 mL). The phases wereseparated and the aqueous phase was extracted with EtOAc (40 mL). Thecombined organic phases were washed with H₂O and brine, then dried(MgSO₄), filtered and concentrated in vacuo. Purification of the cruderesidue by flash column chromatography on silica gel (20% EtOAc/hexane)afforded 326 mg (91%) of 36.

Step 2: Wittig Reaction of 36 to Give Enol Ether 37.

Potassium tert-butoxide (104 mg, 0.93 mmol) was added to a solution ofmethoxymethyltriphenylphosphonium chloride (152 mg, 0.444 mmol) in THF(2 mL) at 0° C. After 30 min at 0° C., a solution of aldehyde 36 (100mg, 0.37 mmol) in THF (1 mL) was added. The reaction mixture was allowedto warm to rt and stirred overnight. The reaction was quenched at 0° C.by the slow addition of H₂O then was partitioned between 10% aqueous HCl(20 mL) and EtOAc (40 mL). The phases were separated and the aqueousphase was extracted with EtOAc (40 mL). The combined organic phases werewashed with H₂O and brine, then dried (MgSO₄), filtered and concentratedin vacuo. Purification of the crude residue by flash columnchromatography on silica gel (20% EtOAc/hexane) afforded 83 mg (76%) ofenol ether 37.

Step 3: Hydrolysis of Enol Ether 37 to Give Aldehyde 38

0.1 M aqueous HCl (90 μL, 0.09 mmol) was added to a solution of enolether 37 (83 mg, 0.28 mmol) in dioxane (2.8 mL). After 1 h at rt, themixture was heated at 60° C. for 2.5 h. The reaction mixture waspartitioned between saturated aqueous NaHCO₃ (10 mL) and CH₂Cl₂ (10 mL).The phases were separated and the aqueous phase was extracted withCH₂Cl₂ (2×20 mL). The combined organic phases were washed with H₂O andbrine then dried (MgSO₄), filtered and concentrated in vacuo.Purification of the crude residue by flash column chromatography onsilica gel (30% EtOAc/hexane) afforded 23 mg (29%) of aldehyde 38.

Step 4. Reduction of Aldehyde 38 to Alcohol 39.

Sodium borohydride (15 mg, 0.40 mmol) was added to a solution ofaldehyde 38 (75 mg, 0.26 mmol) in MeOH (3.4 mL) at 0° C. The mixture wasallowed to warm to rt. After 20 min at rt, the reaction was cooled to 0°C. and quenched by the slow addition of H₂O. The mixture was thendiluted with H₂O (20 mL) and extracted with EtOAc (2×35 mL). Thecombined organic phase was washed with brine, dried (MgSO₄), filteredand concentrated in vacuo. Purification of the crude residue by flashcolumn chromatography on silica gel (50% EtOAc/hexane) afforded 63 mg(84%) of alcohol 39.

Step 5: Acylation of 39 to Give 40.

Alcohol 39 (63 mg, 0.22 mmol) was converted into 71 mg (99%) of acetate40 in accordance with the procedure of Preparation 2, step 4.

Step 6: Deprotection of 40 to Give Phenol 41

2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ, 23 mg, 0.10 mmol) wasadded to a mixture of ether 40 (30 mg, 0.091 mmol) in CH₂Cl₂ (0.9 mL)and H₂O (47 μL) at 0° C. After 1 h at 0° C. the reaction was allowed towarm to rt. After 4 h at rt, the reaction was quenched with saturatedaqueous NaHCO₃ (10 mL). The mixture was extracted with CH₂Cl₂ (3×10 mL).The combined extracts were washed with H₂O and brine then dried (MgSO₄),filtered and concentrated in vacuo. Purification of the residue by flashcolumn chromatography on silica gel (30% EtOAc/hexane) afforded 10 mg(53%) of the title compound (41).

EXAMPLE 66(Z)-7-{(1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-[4-(2-hydroxy-ethyl)-3,5-dimethyl-phenoxymethyl]-cyclopentyl}-hept-5-enoicacid (15zz)

Alcohol 21 (60 mg, 0.15 mmol) and phenol 41 from Preparation 3 (26 mg,0.13 mmol) were converted into the title compound in accordance with theprocedures of Example 15.

EXAMPLE 67(Z)-7-[(1R,2S,3R,5R)-5-Chloro-2-(3,5-dichloro-phenoxymethyl)-3-hydroxy-cyclopentyl]-hept-5-enoicacid isopropyl ester (42b, FIG. 16)

1,8-Diazabicyclo[5.4.0]undec-7-ene (7 μL, 0.05 mmol) was added to asolution of acid 15b from Example 12 (12.5 mg, 0.03 mmol) in acetone(0.3 mL) at rt. After 5 min, 2-iodopropane (15 μL, 0.15 mmol) was added.After 18 h at rt, the solvent was removed under a stream of nitrogen.The residue was diluted with EtOAc (15 mL) and washed with 1.0 M aqueousHCl (10 mL) and brine (10 mL) then dried (Na₂SO₄), filtered andconcentrated in vacuo. Purification of the residue by flash columnchromatography on silica gel (25% EtOAc/hexane→EtOAc, gradient) afforded10 mg (73%) of the title compound (42b) along with 2.5 mg (20%) ofrecovered starting material 15b.

EXAMPLE 68(Z)-7-[(1R,2S,3R,5R)-2-(3,5-Bis-trifluoromethyl-phenoxymethyl)-5-chloro-3-hydroxy-cyclopentyl]-hept-5-enoicacid isopropyl ester (42c)

Acid 15c from Example 15 (7 mg, 0.14 mmol) was converted into 7 mg (92%)of the title compound (42c) in accordance with the procedure of Example67.

EXAMPLE 69(Z)-7-[(1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-(3-trifluoromethyl-phenoxymethyl)-cyclopentyl]-hept-5-enoicacid isopropyl ester (42i)

Acid 15i from Example 24 (17 mg, 0.04 mmol) was converted into 15 mg(80%) of the title compound (42i) in accordance with the procedure ofExample 67.

EXAMPLE 70(Z)-7-[(1R,2S,3R,5R)-5-Chloro-2-(3,5-dimethyl-phenoxymethyl)-3-hydroxy-cyclopentyl]-hept-5-enoicacid isopropyl ester (42u)

Acid 15u from Example 36 (47 mg, 0.13 mmol) was converted into the titlecompound (42u) in accordance with the procedure of Example 67.

EXAMPLE 71(Z)-7-[(1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-(4-hydroxymethyl-phenoxymethyl)-cyclopentyl]-hept-5-enoicacid isopropyl ester (42bb)

Step 1: Acid 15aa from Example 42 (10 mg, 0.026 mmol) was converted into6.5 mg (59%) of isopropyl ester 42aa in accordance with the procedure ofExample 67.

Step 2: Aldehyde 42aa (6.5 mg, 0.015 mmol) was converted into 5.4 mg(83%) of the title compound (42bb) in accordance with the procedure ofExample 43, step 1.

Binding Data

Ki

Competition binding experiments were performed in a medium containingHank's balanced salt solution, Hepes 20 mM, pH 7.3, membranes (˜60 μgprotein) or 2×10⁵ cells from HEK 293 cells stably expressing human EP2receptors, [³H]PGE2 (10 nM) and various concentrations of test compoundsin a total volume of 300 μl. Reaction mixtures were incubated at 23° C.for 60 min, and were filtered over Whatman GF/B filters under vacuum.Filters were washed three times with 5 ml ice-cold buffer containing 50mM Tris/HCl (pH 7.3). Non-specific binding was estimated in the presenceof excess unlabeled PGE2 (10 μM). Binding data fitted to the bindingmodel for a single class of binding sites, using nonlinear regressionanalysis. IC₅₀ values thus obtained were converted to Ki using theequation of Ki=(IC₅₀/(1+[L]/K_(D)) where [L] represents PGE2concentration (10 nM) and K_(D) the dissociation constant for [³H]PGE2at human EP2 receptors (40 nM).

Radioligand Binding

Cells Stably Expressing EP₁, EP₂, EP₄ and FP Receptors

HEK-293 cells stably expressing the human or feline FP receptor, or EP₁,EP₂, or EP₄ receptors were washed with TME buffer, scraped from thebottom of the flasks, and homogenized for 30 sec using a Brinkman PT10/35 polytron. TME buffer was added to achieve a final 40 ml volume inthe centrifuge tubes (the composition of TME is 100 mM TRIS base, 20 mMMgCl₂, 2M EDTA; 10N HCl is added to achieve a pH of 7.4).

The cell homogenate was centrifuged at 19000 r.p.m. for 20 min at 4° C.using a Beckman Ti-60 rotor. The resultant pellet was resuspended in TMEbuffer to give a final 1 mg/ml protein concentration, as determined byBiorad assay. Radioligand binding competition assays vs. [3H-] 17-phenylPGF₂, (5 nM) were performed in a 100 μl volume for 60 min. Bindingreactions were started by adding plasma membrane fraction. The reactionwas terminated by the addition of 4 ml ice-cold TRIS-HCl buffer andrapid filtration through glass fiber GF/B filters using a Brandel cellharvester. The filters were washed 3 times with ice-cold buffer and ovendried for one hour.

[³H-] PGE₂ (specific activity 180 Ci mmol) was used as the radioligandfor EP receptors. [³H] 17-phenyl PGF₂, was employed for FP receptorbinding studies. Binding studies employing EP₁, EP₂, EP₄ and FPreceptors were performed in duplicate in at least three separateexperiments. A 20011 assay volume was used. Incubations were for 60 minat 25° C. and were terminated by the addition of 4 ml of ice-cold 50 mMTRIS-HCl, followed by rapid filtration through Whatman GF/B filters andthree additional 4 ml washes in a cell harvester (Brandel). Competitionstudies were performed using a final concentration of 5 nM [³H]-PGE₂, or5 nM [³H] 17-phenyl PGF₂, and non-specific binding determined with 10⁻⁵Mof unlabeled PGE₂, or 17-phenyl PGF_(2α), according to receptor subtypestudied.

Methods for FLIPR™ Studies

(a) Cell Culture

HEK-293(EBNA) cells, stably expressing one type or subtype ofrecombinant human prostaglandin receptors (prostaglandin receptorsexpressed: hDP/Gqs5; hEP₁; hEP₂/Gqs5; hEP_(3A)/Gqi5; hEP₄/Gqs5; hFP;hIP; hTP), were cultured in 100 mm culture dishes in high-glucose DMEMmedium containing 10% fetal bovine serum, 2 mM 1-glutamine, 250 μg/mlgeneticin (G418) and 200 μg/ml hygromycin B as selection markers, and100 units/ml penicillin G, 100 μg/ml streptomycin and 0.25 μg/mlamphotericin B.

(b) Calcium Signal Studies on the FLIPR™

Cells were seeded at a density of 5×10⁴ cells per well in Biocoat®Poly-D-lysine-coated black-wall, clear-bottom 96-well plates(Becton-Dickinson) and allowed to attach overnight in an incubator at37° C. Cells were then washed two times with HBSS-HEPES buffer (HanksBalanced Salt Solution without bicarbonate and phenol red, 20 mM HEPES,pH 7.4) using a Denley Cellwash plate washer (Labsystems). After 45minutes of dye-loading in the dark, using the calcium-sensitive dyeFluo-4 AM at a final concentration of 2 μM, plates were washed fourtimes with HBSS-HEPES buffer to remove excess dye leaving 100 μl in eachwell. Plates were re-equilibrated to 37° C. for a few minutes.

Cells were excited with an Argon laser at 488 nm, and emission wasmeasured through a 510-570 nm bandwidth emission filter (FLIPR™,Molecular Devices, Sunnyvale, Calif.). Drug solution was added in a 50μl volume to each well to give the desired final concentration. The peakincrease in fluorescence intensity was recorded for each well. On eachplate, four wells each served as negative (HBSS-HEPES buffer) andpositive controls (standard agonists: BW245C (hDP); PGE₂ (hEP₁;hEP₂/Gqs5; hEP_(3A)/Gqi5; hEP₄/Gqs5); PGF_(2α) (hFP); carbacyclin (hIP);U-46619 (hTP), depending on receptor). The peak fluorescence change ineach drug-containing well was then expressed relative to the controls.

Compounds were tested in a high-throughput (HTS) orconcentration-response (CoRe) format. In the HTS format, forty-fourcompounds per plate were examined in duplicates at a concentration of10⁻⁵ M. To generate concentration-response curves, four compounds perplate were tested in duplicates in a concentration range between 10⁻⁵and 10⁻¹¹ M. The duplicate values were averaged. In either, HTS or CoReformat each compound was tested on at least 3 separate plates usingcells from different passages to give an n≧3.

The results of the binding and activity studies, presented in Table 1demonstrate that the compounds disclosed herein are selectiveprostaglandin EP₂ agonists, and are thus useful for the treatment ofglaucoma, ocular hypertension, the other diseases or conditionsdisclosed herein.

In Vivo Examples

(Z)-7-[(1R,2S,3R,5R)-5-Chloro-2-(3,5-dichloro-phenoxymethyl)-3-hydroxy-cyclopentyl]-hept-5-enoicacid (15b) was tested at multiple concentrations in normotensive dogs,dosing once daily for 5 days. At 0.05%, the maximum IOP decrease frombaseline was 4.3 mmHg (30%) at 6 h; the maximum OSH score was 0.6 at 6h. At 0.1%, the maximum IOP decrease from baseline was 4.8 mmHg (34%) at102 h; the maximum OSH score was 1.3 at 6 h. This compound was alsotested in laser-induced hypertensive monkeys, using one single day dose.At 0.1%, the maximum IOP decrease from baseline was 6 mmHg (19%) at 6 h.

(Z)-7-[(1R,2S,3R,5R)-5-Chloro-2-(3,5-dichloro-phenoxymethyl)-3-hydroxy-cyclopentyl]-hept-5-enoicacid isopropyl ester (42b) was tested in normotensive dogs at 0.05%,dosing once daily for 5 days. The maximum intraocular pressure (IOP)decrease from baseline was 3 mmHg (19%) at 6 h; the maximum ocularsurface hyperemia (OSH) score was 0.6 at 74 h. This compound was alsotested in laser-induced hypertensive monkeys, using one single day dose.At 0.01%, the maximum IOP decrease from baseline was 6 mmHg (16%) at 6h.

(Z)-7-[(1R,2S,3R,5R)-2-(3,5-Bis-trifluoromethyl-phenoxymethyl)-5-chloro-3-hydroxy-cyclopentyl]-hept-5-enoicacid (15c) was tested in normotensive dogs at 0.1%, dosing once dailyfor 5 days. The maximum intraocular pressure (IOP) decrease frombaseline was 4.8 mmHg (35%) at 100 h; the maximum ocular surfacehyperemia (OSH) score was 0.9 at 52 h. This compound was also tested inlaser-induced hypertensive monkeys, using one single day dose. At 0.1%,the maximum IOP decrease from baseline was 11 mmHg (30%) at 6 h.

(Z)-7-[(1R,2S,3R,5R)-2-(3,5-Bis-trifluoromethyl-phenoxymethyl)-5-chloro-3-hydroxy-cyclopentyl]-hept-5-enoicacid isopropyl ester (42c) was tested in normotensive dogs at 0.03%,dosing once daily for 5 days. The maximum intraocular pressure (IOP)decrease from baseline was 2.3 mmHg (14%) at 100 h; the maximum ocularsurface hyperemia (OSH) score was 0.7 at 78 h. This compound was alsotested in laser-induced hypertensive monkeys, using one single day dose.At 0.03%, the maximum IOP decrease from baseline was 4 mmHg (11%) at 6h.

(Z)-7-[(1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-(naphthalen-1-yloxymethyl)-cyclopentyl]-hept-5-enoicacid (15e) was tested in normotensive dogs at 0.1%, dosing once dailyfor 5 days. The maximum intraocular pressure (IOP) decrease frombaseline was 5.8 mmHg (41%) at 6 h; the maximum ocular surface hyperemia(OSH) score was 0.8 at 54 h. This compound was also tested inlaser-induced hypertensive monkeys, using one single day dose. At 0.1%,the maximum IOP decrease from baseline was 11.8 mmHg (31%) at 6 h.

(Z)-7-[(1R,2S,3R,5R)-5-Chloro-2-(3,5-dimethyl-phenoxymethyl)-3-hydroxy-cyclopentyl]-hept-5-enoicacid (15u) was tested in normotensive dogs at 0.1%, dosing once dailyfor 5 days. The maximum intraocular pressure (IOP) decrease frombaseline was 6.5 mmHg (46%) at 52 h; the maximum ocular surfacehyperemia (OSH) score was 1.2 at 28 h. This compound was also tested inlaser-induced hypertensive monkeys, using one single day dose. At 0.1%,the maximum IOP decrease from baseline was 9 mmHg (25%) at 2 h.

(Z)-7-[(1R,2S,3R,5R)-5-Chloro-2-(3,5-dimethyl-phenoxymethyl)-3-hydroxy-cyclopentyl]-hept-5-enoicacid isopropyl ester (42u) was tested in normotensive dogs at 0.1%,dosing once daily for 5 days. The maximum intraocular pressure (IOP)decrease from baseline was 4.3 mmHg (30%) at 30 h; the maximum ocularsurface hyperemia (OSH) score was 0.9 at 74 h. This compound was alsotested in laser-induced hypertensive monkeys, using one single day dose.At 0.1%, the maximum IOP decrease from baseline was 8 mmHg (23%) at 6 h.

(Z)-7-[(1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-(3-trifluoromethyl-phenoxymethyl)-cyclopentyl]-hept-5-enoicacid (15i) was tested in normotensive dogs at 0.1%, dosing once dailyfor 5 days. The maximum intraocular pressure (IOP) decrease frombaseline was 2.5 mmHg (16%) at 78 h; the maximum ocular surfacehyperemia (OSH) score was 0.5 at 6 h. This compound was also tested inlaser-induced hypertensive monkeys, using one single day dose. At 0.1%,the maximum IOP decrease from baseline was 10.8 mmHg (28%) at 6 h.

(Z)-7-[(1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-(3-trifluoromethyl-phenoxymethyl)-cyclopentyl]-hept-5-enoicacid isopropyl ester (42i) was tested in normotensive dogs at 0.1%,dosing once daily for 5 days. The maximum intraocular pressure (IOP)decrease from baseline was 2.7 mmHg (19%) at 2 h; the maximum ocularsurface hyperemia (OSH) score was 0.6 at 50 h. This compound was alsotested in laser-induced hypertensive monkeys, using one single day dose.At 0.1%, the maximum IOP decrease from baseline was 4.7 mmHg (14%) at 6h.

(Z)-7-[(1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-(4-hydroxymethyl-phenoxymethyl)-cyclopentyl]-hept-5-enoicacid (15bb) was tested in normotensive dogs at 0.1%, dosing once dailyfor 5 days. The maximum intraocular pressure (IOP) decrease frombaseline was 2.8 mmHg (20%) at 98 h; the maximum ocular surfacehyperemia (OSH) score was 0.6 at 98 h. This compound was also tested inlaser-induced hypertensive monkeys, using one single day dose. At 0.1%,the maximum IOP decrease from baseline was 2 mmHg (6%) at 6 h.

(Z)-7-[(1R,2S,3R,5R)-5-Chloro-3-hydroxy-2-(4-hydroxymethyl-phenoxymethyl)-cyclopentyl]-hept-5-enoicacid isopropyl ester (42bb) was tested in normotensive dogs at 0.1%,dosing once daily for 5 days. The maximum intraocular pressure (IOP)decrease from baseline was 4.6 mmHg (33%) at 100 h; the maximum ocularsurface hyperemia (OSH) score was 0.6 at 30 h. This compound was alsotested in laser-induced hypertensive monkeys, using one single day dose.At 0.1%, the maximum IOP decrease from baseline was 5.5 mmHg (16%) at 6h.

1. A method of treating a disease or condition selected from: glaucoma,ocular hypertension, and baldness, comprising administering an effectiveamount of a compound to a mammal in need thereof, said compound havingone of the formulas shown below:

or a pharmaceutically acceptable salt or a prodrug thereof.
 2. Themethod of claim 1 wherein the compound has the formula

or a pharmaceutically acceptable salt or a prodrug thereof.
 3. Themethod of claim 1 wherein the compound has the formula

or a pharmaceutically acceptable salt or a prodrug thereof.
 4. Themethod of claim 1 wherein the compound has the formula

or a pharmaceutically acceptable salt or a prodrug thereof.
 5. Themethod of claim 1 wherein the compound has the formula

or a pharmaceutically acceptable salt or a prodrug thereof.
 6. Themethod of claim 1 wherein the compound has the formula

or a pharmaceutically acceptable salt or a prodrug thereof.
 7. Themethod of claim 1 wherein the compound has the formula

or a pharmaceutically acceptable salt or a prodrug thereof.
 8. Themethod of claim 1 wherein the compound has the formula

or a pharmaceutically acceptable salt or a prodrug thereof.
 9. Themethod of claim 1 wherein the compound has the formula

or a pharmaceutically acceptable salt or a prodrug thereof.
 10. Themethod of claim 1 wherein the compound has the formula

or a pharmaceutically acceptable salt or a prodrug thereof.
 11. Themethod of claim 1 wherein the compound has the formula

or a pharmaceutically acceptable salt or a prodrug thereof.
 12. Themethod of claim 1 wherein the compound has the formula

or a pharmaceutically acceptable salt or a prodrug thereof.
 13. Themethod of claim 1 wherein the compound has the formula

or a pharmaceutically acceptable salt or a prodrug thereof.
 14. Themethod of claim 1 wherein the compound has the formula

or a pharmaceutically acceptable salt or a prodrug thereof.
 15. Themethod of claim 1 wherein the compound has the formula

or a pharmaceutically acceptable salt or a prodrug thereof.
 16. Themethod of claim 1 wherein the compound has the formula

or a pharmaceutically acceptable salt or a prodrug thereof.
 17. Themethod of claim 1 wherein the compound has the formula

or a pharmaceutically acceptable salt or a prodrug thereof.
 18. Themethod of claim 1 wherein the compound has the formula

or a pharmaceutically acceptable salt or a prodrug thereof.
 19. Themethod of claim 1 wherein the compound has the formula

or a pharmaceutically acceptable salt or a prodrug thereof.
 20. Themethod of claim 1 wherein the compound has the formula

or a pharmaceutically acceptable salt or a prodrug thereof.
 21. Themethod of claim 1 wherein the mammal is a human.
 22. The method of claim21 wherein the disease or condition is glaucoma.
 23. The method of claim21 wherein the disease or condition is ocular hypertension.
 24. Themethod of claim 21 wherein the disease or condition is baldness.